Open access peer-reviewed chapter

Long Non-Coding RNA in Neural Stem Cells Self-Renewal, Neurogenesis, Gliogenesis and Synaptogenesis

Written By

Neetu Singh

Submitted: 29 April 2022 Reviewed: 25 August 2022 Published: 10 October 2022

DOI: 10.5772/intechopen.107375

From the Edited Volume

Recent Advances in Noncoding RNAs

Edited by Lütfi Tutar

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Abstract

Evidence reports the key roles of lncRNAs in several regulatory mechanisms of neurons and other brain cells. Neuronal lncRNAs are crucial for NSCs mediated-neuronal developmental stages like neurogenesis, neuronal differentiation, and synaptogenesis. Moreover, multilineage properties of NSCs and their association to specific cell types render them to identify the commonly accepted biomarkers for the brain. It is important to delineate the correlation between lncRNAs and NSCs fate decisions during neuronal development stages. In this review, we will summarize how NSCs fabricate embryonic tissue architecture of the central nervous system (CNS) and act as residuum in subventricular zone (SVZ) nearby the lateral wall of the lateral ventricles and the subgranular zone (SGZ) of hippocampus dentate gyrus (DG) of the adult brain. Additionally, describe the roles and molecular mechanisms of lncRNAs involved in NSCs self-renewal, neurogenesis, gliogenesis and synaptogenesis over the course of neural development. This will help us to better understand neuronal physiology.

Keywords

  • long noncoding RNAs
  • neurons
  • neuronal development
  • neuronal differentiation
  • neurogenesis
  • synaptic activity
  • synaptic plasticity

1. Introduction

In the central nervous system (CNS), an efficient spatio-temporal regulatory mechanisms play an important role in neural stem cells (NSCs) for the development of neurons and other brain cells. The development and differentiation of the CNS is intricate in nature, and plethora of regulatory factors are involved and express ~40% of lncRNAs [1]. lncRNAs are involved in the early development/differentiation of the nervous system (NS) through NSCs to synaptogenesis [2, 3, 4]. Field et al. [5] constituted pluripotent stem cell (PSC)-derived cerebral cortex organoid (CO) cell cultures which recapitulate the cellular organization and gene expression events observed in fetal tissue. PAX6 (neural progenitors), CTIP2 and TBR1 express during early deep-layer neuron and TBR2 expression is in intermediate progenitors in Human COs at day 35. The ratio of human COs, pluripotency markers such as OCT3/4 were down-regulated, while early neural stem cell markers, including PAX6, were up-regulated during the first week. Subsequently by 5th week TBR1 were strongly expressed in Deep-layer neurons. Gene Ontology (GO) term analysis showed significant enrichment of lncRNA associated with neuronal development along with prefrontal cortex and foetus brain as described in Table 1. On assessing lncRNAs, previously described mammalian conserved lncRNAs MALAT1, NEAT1, H19, PRWN1, and CRNDE and 79 unannotated lncRNAs were observed among the 920 primate-conserved category. Markedly, in week 2 transient expression of lncRNAs (TREX) originated from TREX2174 (RP11-314P15) which includes 19 bp insertion overlay at its transcription start site. Importantly, TREX4039 (extends over AC011306 and MIR217HG) peaks at first or second week human COs and disappears by fifth week. At week 2 of human Cos gene expression specific single cells were processed for scRNA-seq libraries and TREX, which have potential roles in early cortical cell fate specifications were identified as depicted in Table 2. The clusters identified at week 2 (neuroepithelium (NE) cells-cluster of 1261 cells; early-forming Cajal-Retzius (CR) cells-cluster of 356 cells; the cortical radial glia (RG)-cluster of up 2593 cells were converted into clusters of early neurons (26%), intermediate progenitors (11%), mature radial glial (RG) (26%), immature RG (18%), dividing RG (12%), and cell doublets (8%) at week 5 of organoid cells.

Human cell atlasARCHS4
Week 2-GO-Term enrichmentWeek 5-GO-Term enrichmentWeek 2-GO-Term enrichmentWeek 5-GO-Term enrichment
Fetal brainFetal brainMotor neuronMotor neuron
Prefrontal cortexPrefrontal cortexPrefrontal cortexPrefrontal cortex
AmygdalaAmygdalaNeuronal epitheliumSpinal cord
Pineal nightPineal nightCerebellumSpinal cord (bulk)
Pineal dayPineal daySpinal cordCerebellum
Smooth muscleCerebellum peduncleSpinal cord (bulk)Fetal brain
Occipital lobeWhole brainMid brainCingulate gyrus
UterusCardiac myocytesFetal brain cortexSensory neuron
ProstrateCerebellumFetal brainCerebral cortex
Cardiac myocytesOccipital lobeSensory neuronBrain (bulk)

Table 1.

The top 10 enriched GO terms from ARCHS4 [6]; based on publicly available RNA-seq data from human and mouse) and Human Cell Atlas ([7]; based on microarrays of human and mouse tissues) ranked by their combined enrichment score [5].

Name of cellsGene expression markersCluster of single cellsEnrichment of transiently expressed lncRNAs (TREX) at week 2Activity of lncRNA in trans manner
Neuroepithelium (NE) cellsHES3 and NR2F1Cluster of 1261 cellsTREX108 and TREX8168Genes associated with whole brain, superior frontal gyrus, and cerebral cortex suggesting a role in general neural gene networks
Cajal-Retzius (CR) cellsTBR1, EOMES, LHX9, and NHLH1Cluster of 356 cellsTREX4039Induced genes enriched in the ARCHS4 neural epithelium gene set and repressed expression of those associated with superior frontal gyrus and astrocytes
Cortical radial glia (RG)SOX2, EMX2, NNAT, PTN, and TLE4Cluster of 2593cellsTREX5008Induced genes enriched in the ARCHS4 neural epithelium gene set and repressed expression of those associated with superior frontal gyrus and astrocytes

Table 2.

10× Chromium 3′ end scRNA-seq on week 2 human COs gene expression based neuroepithelium (NE) cells, were identified by expression of HES3 and NR2F1, forming a cluster of 1261 cells.

Early-forming Cajal-Retzius (CR) cells expressed TBR1, EOMES, LHX9, and NHLH1, comprising a cluster of 356 cells. The largest cluster strongly expressed cortical radial glia (RG) markers SOX2, EMX2, NNAT, PTN, and TLE4, making up 2593 cells showed discovery of transiently expressed lncRNAs, which have potential roles in early cortical cell fate specifications [5].

The study showed the importance of cellular specificity of lncRNA function [8]; robust regulatory effects on distal genes upon activation/repression of these TREX lncRNAs was also observed (Table 2). In our recent review [9], we have already discussed the mechanisms to identify lncRNA, synthesize lncRNA, transcription of lncRNA and localized processing of lncRNA in nuclear and cellular portions, and their regulatory functions mediated by linking to chromatin alone or by constructing lncRNA-protein-chromatin complexes owing to chromatin modifications and genomic stability, hence influencing pluripotency. LncRNA are also involved in transcriptional and post transcriptional regulation and serve as scaffolds, chromatin modifiers and miRNA sponges have also been explained in our recent review [9]. This review aims to explain the roles and molecular mechanisms of lncRNAs focusing on NSCs self-renewal, neurogenesis, gliogenesis and synaptic excitability over the course of neural development.

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2. Role of NSCs in designing embryonic tissue architectonics of the central nervous system

Embryonically, the neurons of the brain are organized into layers (cortices) and clusters (nuclei), each having different function and interrelation with other neurons. The embryonic neural tube comprises single cell layer thick germinal neuroepithelium (GNE) which encompasses most proliferative neural stem cells. The GNE continues from the outer edge to the lumen of the neural tube [10], the nuclei of GNE exist at discrete levels, hence giving the impression of numerous cell layers in the neural tube. The nuclei move inside GNE as they move forward to different G0/G1, S and M phases of cell cycle. First and foremost, the S phase or DNA synthesis occurs when the nucleus is at the outer border of the neural tube, subsequently the nucleus moves towards lumen of the neural tube as the cell cycle proceeds.

However, after a certain time period some of the GNE-cells stop DNA synthesis and mitosis and migrate and differentiate into neuronal and glial cells outside the neural tube [11, 12]. The dividing cells of GNE have been found in the outer cortex of the adult brain, this was explained by radioactive thymidine studies. The published reports suggested neuroepithelial stem cells split “vertically” instead of “horizontally.” After vertical division, the daughter cell besides the lumen of the neural tube remains affixed to the ventricular surface (and persists as stem cells in the ventricular zone), while the other daughter cell migrates away [13]. This ultimate vertical division is the terminal division and origination of a neuron happens. The cells which originate late move through GNE and form the most superficial regions of the cortex. Consecutive differentiation is based on the inhabitancy of the new neurons once outside the GNE [14, 15]. The process of division persists i.e., the cells next to the lumen sustain division and are exported outwards to the lumen. In such a manner they form a second layer and sequential addition of more cells derived from GNE thickens and widens the outermost layer and forms mantle (or intermediate zone). The GNE itself acts as a ventricular zone (later known as ependyma that embraces neural stem cells). Further, the cells of the mantle zone differentiates both in neurons and glia. The axons of neurons make connections and move away from the lumen while glial cells form sheath around axons and these are suggested as white matter. While the neuronal cell bodies represent the grey matter.

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3. Spinal cord and medulla assembly

In the spinal cord and medulla, three-zone decorum first-ependymal, second-mantle, and third-marginal layers are maintained throughout development. The grey matter (mantle) is a butterfly-shaped structure and is surrounded by white matter; both grey and white matter are enclosed by the connective tissue. Further, on maturation the neural tube is divided into dorsal and ventral halves through a longitudinal groove, the sulcus limitans. The dorsal portion receives input from sensory neurons, whereas the ventral portion is intricated in performing various motor functions.

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4. Cerebellar structure

In cerebellum the different neurons which migrate outside the GNE through cell migration, further undergoes differential neuronal proliferation, and selective cell death that creates modifications in the three-zone pattern (ependymal, mantle, and marginal layers).

In the cerebellum, a small quantity of neuronal precursors i.e., neuroblasts derived from GNE either enter the marginal zone to form clusters of neurons called nuclei or migrate to the outer surface of the neural tube to form a new germinal zone. Each single nucleus of the marginal zone works as an individual functional unit, and connects to the outer layers of the cerebellum and other parts of the brain. The new germinal zone forms the outer layer of the developing cerebellum and is also known as the external granule layer-EGL (two cells thick layer. The outer layer of the EGL is composed of dividing neuroblasts, while the inner layer of EGL comprises postmitotic neuroblasts. The latter are the precursors of the preeminent neurons of the cerebellar cortex and the granule neurons. Granule neurons are the major component of the internal granule layer-IGL that migrates back to white matter of developing cerebellum. Concurrently, the ependymal layer (ventricular zone of GNE) differentiates into neurons and glial cells which include the unique Purkinje neurons. Purkinje neurons interact to form electrical synapses (unlike chemical synapses, there is direct interaction between presynaptic and postsynaptic neurons and also support granule neurons. These neurons secrete a specific morphogen Sonic hedgehog (SHH), which maintains the division of granule neuron precursors (neuroblasts) in the EGL [16].

Each Purkinje neuronal cell body is shaped like a flask and has a large, flat, highly branched thread like extensions creating a dendritic Arbor. This helps in forming hundreds of thousands connections (synapses) with other cells like Bergmann glial cells and granule cells. The axon of each Purkinje neuron connects to neurons in the deep cerebellar nuclei and transmits impulses to the region of cerebellum which controls movement.

The evolution of spatial arrangement of neurons is an essential process for the development and functioning of the cerebellum. Positioning of young neurons is under glial guidance [17, 18]. Importantly, the granule cell precursors (neuroblasts) move forward through adhesion on the long axonal processes of the Bergmann glia [19, 20]. The neural-glial reciprocal interaction between glial cells and neuroblasts [17, 21] is held up by adhesion protein called astrotactin that assists in adhesion of neurons to the glial cells [22, 23].

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5. Cerebral structure

The three-zone positioning pattern cerebellum first-ependymal, second-mantle, and third-marginal layers of the neural tube is modified to vertical and horizontal positioning in the cerebrum.

Vertical positioning shows different vertical layers which interact with one another. As in cerebellum, in cerebrum, some of the neuroblasts move outwards from GNE and form the mantle zone and travel under glial guidance along the white matter to produce an additional layer of neurons at the outer layer of the cerebral cortex. This additional layer of grey matter (mantle) is called the neocortex. Neocortex is 2–5 mm thick, present on the surface of brain time-dependently differentiates into six layers (molecular layer, external granular layer, external pyramidal layer, internal granular layer, ganglionic layer and multiform layer) of neuronal cell bodies. Although layers are premature in nature and the maturity is not completed until the middle of childhood. Each vertical layer of the neocortex is unique and holds a specific function based on the types of neurons, and their connections with other neurons. For example, the inputs sent by thalamus are received by the neurons of layer 4, while output back to the thalamus is sent by the neurons of layer 6.

Horizontal positioning of the layers in cerebrum is more complex and they approximately form almost 40 regions that are regulated physiologically and have specific functions. For example, neurons in vertical cortical layer 6 horizontally possess both “visual cortex” and “auditory cortex”. Auditory cortex is more anterior in position than the visual cortex. Visual cortex projects axons to the lateral geniculate nucleus of the thalamus (for vision), while auditory cortex projects axons to the medial geniculate nucleus of the thalamus (for hearing).

The vertical and horizontal arrangement in cerebrum depends on numerous multilineage neuroblasts derived from GNE. Further, on terminal mitotic division most of the neuroblasts of ventricular (ependymal) progress under glial guidance and lead to the formation of cortical plates located at the outer surface of the cortex of cerebrum.

To conclude, the neuroblasts with the early origin derived from GNE form the layer adjacent to the ventricle while neurons of later origin migrate through GNE and set apart to form the more exterior layers of the cortex. This positioning of cells forms an “inside-out” descent of expansion [24]. The neuroblast of the ventricular (ependymal) zone divides into neurons and glial cells in any of the cortical layers [25]. However, the fates of neuroblasts depend on the terminal division. The neuroblasts early in development are in their mid-S phase i.e., are in the way of division i.e., final division is not complete, hence likely become any neuron (for instance neurons of layers 2 or 6), at later stage of development of neuroblasts final mitosis is complete that give rise only to upper-level (layer 2) neurons [26]. The migration of the majority of these young neurons occurs in a radial manner on glial processes [27]. The migration initiates from the ventricular zone to the cortical plate. After neurogenesis, the generated young neurons (~12%) migrate laterally from one region of the cerebral cortex into another [28]. Further, the positioning of young neurons in different cortical areas are designated to unique functional domains. Once the neuronal cells make an appearance at their final designated cortical area, they may produce specific adhesion molecules that sort them together as brain nuclei [29].

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6. Role of adult neural stem cells (NSCs) in neurogenesis

The cortical regions are composed of abundant neurons and glial cells produced from the differentiation of GNE-derived neuronal precursor cells/neuroblasts, which are self-sufficient to renew themselves as well as differentiate into multilineage neurons in the brain [30]. The above process of producing neurons and glial cells are termed neurogenesis and gliogenesis, respectively [31]. The largest NSCs/neuronal precursor cells/neuroblasts niches all through the life are essentially located in the adult ventricular-subventricular zone (V-SVZ) adjacent to the walls of the lateral ventricles [32] and the subgranular zone (SGZ) in the dentate gyrus of the hippocampus where new dentate granule cells are produced.

6.1 NSC model in the adult subventricular zone under basal conditions

V-SVZ produces large number of neuroblasts which travel a long distance through the rostral migratory stream (RMS) to the olfactory bulb (OB) in form of a chain, where they finally differentiate into granule cell type local interneurons [33]. Further, once reaching the core of the OB, immature neurons separate from the RMS through radial migration and then migrate towards glomeruli and differentiate into various subtypes of periglomerular (PG) interneurons. PG interneurons interconnect with the apical dendrites (often lack axons) of mitral and tufted cells inside the glomeruli [34]. The majority of interneurons are GABAergic granule cell neurons, which lack axons and form dendro-dendritic synapses with lateral dendrites of mitral and tufted cells in the external plexiform layer. In addition, few number of GABAergic PG interneurons and small percentage of interneurons are dopaminergic in nature. One report also suggested that very low percent of new interneurons are glutamatergic juxtaglomerular neurons in nature [35]. Transcript based markers have been identified for the five developmental stages of adult SVZ neurogenesis of the lateral ventricle and OB [1] activation of radial glia-like cells (GFAP, Vimentin and nestin positive) in the SVZ zone in the lateral ventricle (LV); [2] proliferation of transient amplifying cells/progenitor cells (Mash1 and low amount of nestin); [3] produce neuroblasts (Dlx2 positive) that migrate to OB; [4] subsequent chain migration of neuroblasts (Dlx2 positive) within the RMS and radial migration of immature neurons (Dlx2 and DCX positive) in the OB; [5] Synaptic interaction through interneurons (NeuN positive) and maturation of GC and PG neurons in the OB (reviewed by [33]) .

6.2 NSC model in the adult hippocampus under basal conditions

Adult SGZ in the dentate gyrus of the hippocampus possess proliferating radial and non-radial neuronal precursor cells that generate intermediate progenitors/transit amplifying cells, which in succession generate neuroblasts.

The multi-lineage radial precursors i.e., radial glia-like cells (RGLs or Type-1 cells) in dentate gyrus of adult hippocampus are identified through expression of transcripts like nestin, GFAP and Sox2. Besides transcript markers a distinguishing feature RGL possesses is radial branch which extends through the granule cell layer. Single RGL undergoes several rounds of self-renewal and differentiation to produce both neurons and astrocytes for a long period, displaying characteristic stem cell properties by each RGLs as evidenced through in vivo clonal assays [36].

Quiescent RGLs once triggered from quiescence stage i.e. G0 phase, RGLs moves towards formation of specific cell types like RGLs, non-radial precursors, proliferative intermediate progenitors (IPCs, or Type-2 cells) and astroglia, excluding the oligodendrocyte lineage. Later on the fate of RGLs may be decided whether they remain in a proliferative state, return to quiescence, or differentiate into an astrocyte.

Non-radial precursors generate new neurons in the adult SGZ and act as primary precursors [37]. They lack any radial process and few cells present as parallel extensions to the dentate granule cell layer. Unlike RGL, non-radial precursors express Sox2, but not GFAP [38] and more proliferative i.e., mostly present in cell cycle [37, 38]. They may or may not show involvement of IPCs and may generate new RGLs or astroglia, while maintaining the precursor state [36].

IPCs of the SGZ region of dentate gyrus rapidly proliferate and possess small tangential processes expressing Tbr2 as transcript marker [39]. They are derived from both radial and non-radial precursors [36, 38]. Afterwards they convert into secondary transient amplifying precursors and start expressing DCX and Prox1, markers of committed immature neurons [39]. IPCs re-enter cell cycle for self-renewal or produce astroglia or maintain as precursors over a long duration remains unclear.

In adult dentate non-neurogenic areas and SGZ region enrichment of another, progenitor population of NG2 cells have been identified [40] Major features of NG2 cells are long wispy processes, expression of specific proteogylcan NG2 as well as PDGF, Sox10 and Olig2 [41] has been observed. Presence of NG2 cells and oligodendrocytes in non-neurogenic areas differentiate them from RGLs in the adult SGZ [36] suggesting that they may have derived from different precursor populations with different embryonic origins. The consensus remains that NG2 cells may produce astroglia during development, and oligodendrocyte generation in the adult nervous system [41].

Astroglia, non-neuronal quiescent precursor cell type as proposed by absence of nestin expression, are a prospective third precursor population in the adult SGZ. Major characteristic features are horizontal or bushy morphology and expression of GFAP, S100β and Aldh1l1 markers [42]. The new astroglia generate from RGLs in the adult SGZ; afterwards they migrate to the hilus or molecular layer [36]. Hence, neuroblasts from NSCs in SGZ migrate short distances into the granule cell layer and mature into neurons, then integrate into functional circuits [43].

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7. The effect of lncRNA on NSCs/NPCs pluripotency

Cell type- and tissue-specific long non-coding RNAs (lncRNAs) incorporate varying classes of transcripts that can control various fundamental molecular and cellular processes in organ development, disease and cancer. Here we will discuss the differential expression and unique function of lncRNAs in human brain development.

LncRNAs are present amply and specifically in different lineages of neurogenic cell-types which plays an important role in neuronal development [8]. For instance, Liu et al. [44] identified cell type-specific lncRNA and mRNA transcript pairs in developing neocortex; (a) radial glia-specific lncRNA LOC646329-mRNA PAX6, (b) maturing neuron-specific lncRNA LINC00599-mRNA RTN1, (c) interneuron-specific lncRNA DLX6-AS1-progenitor and differentiated cell-expressed mRNA NNAT. Maturing neurons of the cortical plate (CP) were enriched with LINC00599. The subpial granular layer interneuron showed predominance of unique DLX6-AS1 [45, 46].

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8. The function of lncRNAs in neurogenesis/neural differentiation

LncRNAs play a pivotal role in regulating epigenetic elements in NPCs or NSCs differentiation and neural development [47, 48]. Spatial and temporal expression of lncRNAs plays a very crucial role in neuronal development in the developing CNS [49]. However, the abundance and specificity of lncRNAs in different neurogenic cell-types or the specific functions show their involvement in development and cellular identity in the nervous system [1, 8].

Recently, a gene expression atlas of embryonic neurogenesis in Drosophila revealed complex spatiotemporal regulation of lncRNAs. This involved a significant set of 13 lncRNAs, on illustration they represented [1] time dependent appearance at subcellular and cellular levels, [2] moderate to excess expression in cytoplasmic or nuclear regions [3] were involved in precise RNA processing (for example splicing and nuclear-cytoplasmic commutation), during critical events in neurogenesis in Drosphila Table 3 [50].

CR30009CR30009 is spliced and primarily exported to the cytoplasmIncreased expression in the early IC and in NBs (4–6 h and 6–8 h) constitutes the earliest neuroblast marker of the glial lineage
However, was most highly enriched in glial cells stage 9/10 and stage 13/14
Specific expression in NBs and shows increased expression in glial cells
CR43283 (also known as cherub)Specifically localized to the cytoplasm throughout embryogenesis and is clearly spliced, but harbors no coding potential and showed dynamic temporal regulationExpression of cherub was strongly enriched in the earliest neuroblasts at 4–6 h, but enrichment quickly decreased in later neuroblasts (6–8 h); however, over time cherub became specifically expressed being strongly enriched in differentiated neurons and glia by the end of neurogenesis at 18–22 hSpecific expression in NBs and shows increased expression in differentiated neurons and glia
CR32730Moderately enriched in the nuclear fraction in early and late embryosCR32730 first detected in 4-6 h neuroblasts and was moderately enriched at 8–10 h in the neuronal, but not in the glial, populationSpecific expression in NBs and shows increased expression in early neurons
CR46003CR46003 was one of the most abundant and did not exhibit clear subcellular enrichment in either early or late embryosFirst detected in the ventral column and was most highly enriched in early neuroblasts, but expression persisted in neuroblasts and early neuronsSpecific expression in NBs and shows increased expression in early neurons
CR44024Not predicted to exhibit distinct subcellular localization in early (6-8 h) embryos, but was moderately enriched in the cytoplasm at the end of embryogenesis (18–22 h)Was first enriched in early neuroblasts and persisted through neuronal differentiation, and is predicted to be excluded from the intermediate and ventral columns and gliaSpecific expression in NBs and persistent expression in neurons

Table 3.

A list of high-confidence set of lncRNAs classified time dependently; distinct subcellular localization patterns and cell-specifically; moderate to overabundance in cytoplasmic or nuclear regions; and involved in highly specific RNA processing in neurogenesis in Drosphila.

Biological materials studied over the time course of neurogenesis: intermediate column (IC); ventral column (VC); neuroblasts (NBs); neurons; glia. Markers specifically used for RNA-FISH was NBs, Pros; neurons, Elav; glia, Repo (4–6 and 6–8 h (IC, VC, NBs); 6–8, 8–10 and 18–22 h (neurons and glia)) [50].

Interestingly, lncRNAs have undergone specific adaptive functions like selective loss during the evolution of neurogenesis [51]. LncRNA was a key determinant in NSCs or NPCs during cell-fate determination. Additionally, specific lncRNA types are involved in the different stages of NPCs or NSCs differentiation. The neuronal and astrocytic differentiation have been well explained based on a plethora of differentially expressed epigenetically modified lncRNA. It has also been suggested that different lncRNAs have biasness for neuronal differentiation compared to astrocytic differentiation. Although astrocytic differentiation is related more to the sense lncRNAs (lncRNA transcribed from the sense strand of exons possessing coding genes) [52]. Besides, the above functions lncRNAs also participate in synchronizing the fate of NSC differentiation into glia and neurons under physiological and pathological conditions [53, 54]. An overview of lncRNA involved in neurogenesis/neuronal differentiation, gliogenesis or synaptogenesis has been well described in Table 4.

LncRNA nameMechanismBiological functionReferences
Sox2otCpG island of Sox2, interacts with transcription factor YY1 and suppresses the expression of Sox2Prohibit NSCs proliferation and advance neuronal differentiation[55]
RMSTTarget Sox2 promoter regionPromote neurogenesis[56]
Kdm2b (also known as Kancr)Bind with hnRNPAB and activate Kdm2b gene expressionCauses early neuronal differentiation of cortical projection neurons, hence promotes neurogenesis[57]
PauparBind with local epi-regulatorygenes-Pax6 and KAP1 through H3K9me3 depositionPromote neurogenesis in neuroblastoma cells[58, 59]
Gm21284Interact with miR-30e-3p, miR-431 and miR-147Inhibit NSCs proliferation while promote NSCs differentiation[60]
1604miR-200c/ZEB1/2 axisPromote neural differentiation[61]
Rik-201Activated by C/EBPβ, miR-96/Sox6Enhance neural differentiation[62]
Rik-203miR-467a-3p/Sox6, miR-101-3a/GSK-3βEnhance neural differentiation[62, 63]
MEG3Act as a negative regulator of miR-128-3p while induced by the cAMP/response element-binding protein (CREB) pathwayPromotes neuron differentiation[64]
Malat1Activate ERK/MAPK, inhibit PPAR/p53Promote neural differentiation in neuroblastoma-derived Neuro-2a (N2a) cell[65]
PnkyInteract with RNA-binding protein (RBP)-PTBP1Inhibit neural differentiation and neurogenesis[30, 66]
lncR492Interact with HuR and activate Wnt signallingInhibit neural differentiation of mouse embryonic stem cells[67]
BDNF-ASTargeting activating potassium uptake system protein (TrkB) signaling pathwayInhibit eNSCs-derived neurite outgrowth and neural apoptosis[68]
UCA1miR-1 and its target Hes1Promote NSCs differentiation to astrocyte not to neuron[54]
lnOPClnOPC binds to upstream sequences of OLIG2Promotes OPCs differentiation and oligodendrogenesis[69]
lncOL1Form a complex with Suz12, an oligodendrocyte maturation promoterPromote oligodendrogenesis by promoting early maturation/differentiation of oligodendrocytes in neural development[70]
lnc158Promote regulatory transcription factor-nuclear factor-IB NFIB expressioPromote oligodendrogenesis through enhanced oligodendrocyte-related genes expressions like and enhanced induction of oligodendrocyte lineage differentiation[71]
Pcdh17it (immature lncRNa)Oligodendrogenesis marker identified in new-born immature OLs[72]
OLMALIN/-ASOLMALINCAS, maps to the first exon of the dominant isoform of OLMALINCRegulate oligodendrocyte maturation related genes[73]
Synage (includes three isoforms of Gm2694)Synage as a sponge for the sponge to microRNA miR-325-3p, act as scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complexRegulating synaptic stability in cerebella as distributed in the cytoplasm and synapses of cerebellar cells[74]
GM12371Nuclear-enrichedProlific transcriptional regulator critical for synapse function in hippocampal neurons[75]
Gm2694 (alias AK082312)Enriched expression in the mouse cerebellar cortex[76]
Gm2694
lncRNA (alias linc1582)
Associated with neuroectoderm differentiation[77]
Gm2694
(alias Trincr1) was documented to
Regulate FGF/ERK signalingSelf-renewal of NSCs[78]

Table 4.

The roles of lncRNAs on NSCs differentiation/neurogenesis, oligodendrogenesis and synapse stability.

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9. The function of lncRNAs in neuronal differentiation

LncRNAs are cardinal for neuronal differentiation and for neurogenesis. They are specific to the brain region, especially SVZ, DG or Olfactory Bulb (OB). They exert their functions via interacting with transcription factors or binding to the promoter or enhancer regions of neighbouring/target genes, also act as competing endogenous RNA (ceRNA) against synergistic binding sequences of miRNA or are crucial signaling pathway modulators which regulate chromatin modification, transcription, and post-transcription.

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10. Effect on lncRNA target genes expression

LncRNAs regulate neural development by binding to the proximal regions of the protein-coding genes expressions. Most importantly, evolutionarily conserved, nuclearly localized lncRNA Sox1 overlapping transcript (Sox1ot) and Sox2 overlapping transcript (Sox2ot) were identified in the developing brain. Overlapping transcripts Sox1ot and Sox2ot imbricate with Sox1 and Sox2 protein coding transcripts, respectively [79, 80]. Protein coding Sox1 and Sox2 transcripts function as pluripotent transcription factors to maintain the stemness of NPCs and NSCs [81]. Sox1ot and Sox2ot are highly expressed during neural development and are directly proportional to the Sox1 and Sox2 transcription factors abundance respectively [55, 82]. Mechanistically, overlapping transcript Sox2ot interacts with the transcriptional regulator YY1 and binds to CpG island which is present in the proximity of Sox2 locus and subsequently suppresses the Sox2 expression to restrain stemness of NSCs and NPCs [55]. LncRNA rhabdomyosarcoma 2-associated transcript (RMST) binds with promoter regions of Sox2 and regulates the downstream target genes and is critical for neurogenesis [56]. Another, lncRNA Kdm2b is uniquely transcribed from the bidirectional promoter along with Kdm2b. Epigenetically, lncRNA Kdm2b binds in cis manner with hnRNPAB and manages Kdm2b’s transcription. Although lncRNA Kdm2b expression is transient and occurs only during early neuronal differentiation of cortical projection neurons [57]. LncRNA Paupar, regulates the function of transcriptional/epigenetic regulatory factors and modulates neuroblastoma cell growth. Most importantly, it directly binds to KAP1, which induces H3K9me3 methylation and modulates the expression of downstream target genes important for neuronal proliferation and differentiation. LncRNA Paupar epigenetically modulates (by binding H3K9me3 in cis manner) and controls Pax6 mediated neural differentiation and olfactory bulb neurogenesis [58, 59].

11. lncRNA as competing endogenous RNA (ceRNA) against miRNA

LncRNAs participate in neural development via acting as ceRNA of miRNA and indirectly regulate transcript expression in the cytoplasm [61, 83].

LncRNA Gm21284 promotes differentiation of NSCs to hippocampal cholinergic neurons by binding to miR-30e-3p, miR-431 and miR-147 and on silencing miRNAs impedes NSCs proliferation and enhances NSCs differentiation [60]. LncRNA1604 act as sponge to miR-200c and regulates important transcription factor zinc finger E-box binding homeobox1/2 (ZEB1/2) axis which promotes neural differentiation and on silencing miR-200c repress neural differentiation [61]. LncRNA isoforms also play an important role in neurogenesis. For instance, lncRNA RiK has two variants, Rik-201 and Rik-203. Both these variants get activated by CCAAT/enhancer-binding protein β (C/EBPβ) which are induced during neurogenesis. Mechanistically, Rik-201 triggers C/EBPβ, miR-96/Sox6 axis and [62] and lncRNA Rik-203 induces miR-467a-3p/Sox6, miR-101-3a/Glycogen Synthase Kinase-3β (GSK-3β) [62, 63] to promote neural differentiation. LncRNA MEG3 is also engaged in the process of neuron differentiation. Although it acts as a negative regulator of miR-128-3p it induces the cAMP/response element-binding protein (CREB) pathway [64].

12. LncRNAs as key signalling pathway modulators

LncRNAs moreover can contribute to neural differentiation through NSCs and may function as a key member of the signaling pathway. Neurite outgrowth is an essential act in the early neuronal-differentiation and self-renewal. The lncRNA Metastasis-associated lung adenocarcinoma transcript1 (Malat1) is a requisite for neurite growth in in vitro differentiation of neuroblastoma-derived Neuro-2a (N2a) cell as a model. Knockdown of Malat1 impeded neurite outgrowth and enhanced cell death in N2a cells. This owes to suppression of Mitogen-Activated Protein Kinase (MAPK) and activation of Peroxisome proliferator-activated receptor (PPAR) and p53 signalling pathways [65].

13. LncRNAs mediated repression of neuronal differentiation

As described above, most of the highly expressed lncRNAs promote neuronal differentiation, however, some other neuronal lncRNAs were revealed which blocks neuronal differentiation and plays an important role in brain development.

Nuclear localized lncRNA Pnky, was determined to be involved in neuronal development via inhibiting neuronal differentiation. Specifically, Pnky is expressed selectively in neural tissues that are enriched in SVZ-NSCs which are suppressed into mature neurons. Pnky binds to the pre-mRNA splicing regulator RNA-binding protein (RBP) polypyrimidine tract-binding protein (PTBP1). On silencing either Pnky or PTBP1 alters splicing signature of expressed mRNAs in the cell and subsequently induces neurogenesis in SVZ-NSCs. Hence, inverse correlation has been observed between expression of Pnky-PTBP1 complex and neurogenesis [30, 66]. Another lncRNA lncR492 acts as inhibitor of neuroectodermal differentiation via interacting with mRNA binding protein HuR and activating the Wnt signaling pathway [67]. Zhang et al. reported dose-dependent over expression of lncRNA brain derived neurotrophic factor antisense (BDNF-AS), inhibits neural growth in ketamine-treated mouse embryonic NSC-derived neurons. SiRNA mediated silencing of BDNF transcript expression improved neural apoptosis; inhibited neurite growth in NSC-derived neurons through stimulating potassium uptake system protein (TrkB) signaling pathway [68].

14. Role of lncRNAs in regulation of gliogenesis

Recent reports suggest that radial glial (RG) cells are considered for glial lineage along with a subpopulation of astrocytes. RG as matter of fact act as the NSCs that serve as progenitors for many differentiated neurons and glial cells during development and in the postnatal brain give rise to adult SVZ-NSCs that continue to produce neurons throughout adult life [84]. Importantly, at the inception of cortical development, NSCs or NPCs consecutively give rise to deep layer neurons trailed by surficial layer neurons; at later phase of cortical development, NSCs annihilate neurogenesis and move towards gliogenesis to attain gliogenic capability [85, 86]. Temporal NSCs transition from neurogenesis to gliogenesis is a prerequisite for proper cortical development [86, 87].

Several lncRNAs are considered as key regulators during neuronal-glial fate specification and oligodendrocyte lineage maturation. Time dependent overexpression of human urothelial carcinoma associated 1 (UCA1) was able to decide the direction of NSCs differentiation. Knockdown of UCA1 suggested suppression of NSCs proliferation and differentiation with decreased expression of nestin and the enhanced formation of the neurosphere. Further the silencing of UCA1 repressed NSCs differentiation into astrocytes rather NSCs were directed to differentiate as neurons due to the overexpression of miR-1 expression and decreased expression of its target gene-Hes1. Hence, UCA1 regulated the NSCs proliferation and differentiation through regulating Hes1 expression [54].

Dong et al. screened 5000 lncRNAs and identified lncRNAs that are modulated during oligodendrocyte precursor cell (OPC) differentiation from NSCs and play an essential role in oligodendrogenesis. Lnc-OPC was overexpressed in OPCs and is found to be highly conserved among placental mammals and predicts its role in brain development. Mechanistically, lnc-OPC binds to upstream regulatory elements of OLIG2 and is directly proportional to the OLIG2 expression. Hence, overexpression of lnc-OPC enhances OPCs differentiation and oligodendrogenesis [69].

LncRNA has also emerged as an important regulator in oligodendrocyte mediated myelination and plays a crucial role in development and function of CNS [88, 89]. This was supported by dynamic co-expression signature of lncRNAs with protein coding genes at different stages of oligodendrocyte growth and myelination. Most importantly, highly conserved chromatin-associated lncRNA-lncOL1 has been identified during oligodendrocyte growth and myelination. Genetic knockdown of lncOL1 causes aberrations in myelination and remyelination processes after injury, while gain of function induces early oligodendrocyte differentiation i.e., maturation in neural development. Mechanically, lncOL1 forms a complex with a by binding to the promoter region of a member of polycomb repressive complex 2 (Suz12), involved in oligodendrocyte maturation [44]. Another lnc158 upregulates in NSCs and stimulates downstream various oligodendrocyte-related genes expressions including DNA binding transcription factor-nuclear factor-IB (NFIB) that regulates oligodendrocyte lineage differentiation [71]. Additionally, immature OL-specific lncRNA-Pcdh17 is a specific marker for newly born immature OLs and has been identified both in developing and adult forebrain of mice [72]. Interestingly, lncRNA oligodendrocyte maturation-associated long intervening non-coding RNA (OLMALINC) and its antisense counterpart, OLMALINCAS, both are equivalently and abundantly expressed in the white matter of human frontal cortex as opposed to grey matter and peripheral tissues and basically take part in modulation of human oligodendrocyte maturation related genes. OLMALINCAS, maps to the first exon of the major isoform of OLMALINC [73].

15. The role of lncRNAs in synaptogenesis

Synaptic stability in the developing and adult nervous system results due to the late phase long-term potentiation i.e., a continuous strengthening of synapses for long lasting increase in signal transmission between two neurons. The role of lncRNAs in modulating synaptic stability is ambiguous. Wang et al. [74], reported that cerebellum of the brain shows increased expression of lncRNA, Synage, to regulate synaptic stability. The lncRNA mediated synaptic stability is either lncRNA acting as a sponge or as a scaffold. As a sponge lncRNA Synage binds to miR-325-3p and alters the expression of downstream cerebellar synapse organizer identified in mouse, rhesus macaque, and human. Additionally, lncRNA Synage serves as a scaffold for rearranging the positioning of the LRP1-HSP90AA1-PSD-95 complex in Parallel fibre (PF)-Purkinje cell (PC) synapses. Knockdown of synage collapses cerebellar phenotype and leads to cerebellar degeneration, death of neurons, decline in synapse density which relates to synaptic pruning, decreased synaptic growth and synaptic plasticity during cerebellar development. Hence, the lncRNA Synage plays a major role in regulating synaptic stability and plays a crucial role during cerebellar development. GM12371 (nuclear enriched [75]) and Gm2694 (cerebellar cortex enriched [76]) (alias AK082312) also acts as a transcriptional regulator of synapse function.

16. Conclusion

Neural development related to NSCs/NPCs which constructs embryonic tissue architecture of CNS as well as exist as remnant in subventricular zone (SVZ) nearby the lateral wall of the lateral ventricles and the subgranular zone (SGZ) of hippocampus dentate gyrus (DG) of the brain is considered as a complex phenomenon. Advanced large-scale genome-wide RNA sequencing has been performed in various neuronal cells over the course of neural development to understand NSC self-renewal, neurogenesis, gliogenesis and synaptogenesis. This review has described in detail the functional roles of lncRNAs as ceRNA, by regulating proximal protein-coding genes expressions, and epigenetic modulations in regulation of NSCs/NPCs self-renewal, proliferation and differentiation into neuron or glial cells and synaptogenesis. This suggests that lncRNAs might be employed as potential selection biomarkers for identifying or screening suitable NPCs/NPCs. Importantly, a spatiotemporal expression of lncRNA as atlas of embryonic neurogenesis in Drosophila revealed a high- confidence set of 13 lncRNAs will open a new era of lncRNA based NSCs mediated neurogenesis and may help us to better understand the neuronal physiology. However, most of their function remains to be explored, more novel lncRNAs and their molecular mechanisms remain to be found and probed in-depth yet.

Acknowledgments

A special thanks to my Dr. Sanjay Kumar Singh for inspiring me to write this article and for financial support.

Abbreviations

Aldh1l1aldehyde dehydrogenase 1 family member L1
ARandrogen receptor
BDNFbrain-derived neurotrophic factor
C/EBPβCCAAT/enhancer-binding protein β
ceRNAZEB1/2zinc finger E-box binding homeobox1/2
CNScentral nervous system
COcerebral cortex organoid
CPcortical plate
CRCajal-Retzius
CREBcAMP/response element-binding protein
CTIP2COUP-TF-interacting protein 2
DCXdoublecortin
DGdentate gyrus
Dlx2Distal-Less Homeobox 2
EGLexternal granule layer
ERKextracellular signal regulated kinase
ESCsembryonic stem cells
GSK-3βglycogen synthase kinase-3β
IGLinternal granule layer
IPCsintermediate progenitors
IZintermediate zone
Kdm2blysine demethylase 2B
LncRNAslong non-coding RNAs
LVlateral ventricle
GFAPglial fibrillar protein
Malat1metastasis-associated lung adenocarcinoma transcript1
MAPKmitogen-activated protein kinase
MEG3maternally expressed gene 3
MSNP1ASMoesin pseudogene 1 antisense
N2aNeuro-2a
NEneuroepithelium
NEAT1nuclear paraspeckle assembly transcript 11
NeuNneuronal nuclei
NFIBnuclear factor-IB
NG2polydendrocytes
NotchNotch receptor
NPCsneural precursor/progenitor cells
NSCsneural stem cells
OBolfactory bulb
OCT3/4POU class 5 homeobox 1
Olig2oligodendrocyte transcription factor
OPColigodendrocyte precursor cells
OLMALINColigodendrocyte maturation-associated long intervening non-coding RNA
PauparPAX6 Upstream Antisense RNA
PAX6Paired Box 6
PCPurkinje cell
PDGFplatelet-derived growth factor
Pnkylong intergenic non-protein coding RNA PNKY
PFparallel fiber
PPARperoxisome proliferator-activated receptor
Prox1Prospero Homeobox 1
PSCpluripotent stem cell
PTBP1RNA-binding protein (RBP)-polypyrimidine tract-binding protein
RGLsradial glia-like cells
RBPRNA-binding protein
RGradial glial
RMSrostral migratory stream
RMSTrhabdomyosarcoma 2-associated transcript
RPS10P2-AS1ribosomal protein S10 pseudogene 2 anti-sense 1
S100βS100 calcium-binding protein B
SGZsub-granular zone
SHHsonic hedgehog
Sox10SRY-related HMG-box 10
Sox1otSox1 overlapping transcript
Sox2otSox2 overlapping transcript
Suz12polycomb repressive complex 2
SVZsubventricular zone
TALNEC2tumor associated lncRNA expressed in chromosome 2
TBR1T-box brain transcription factor 1
TBR2T-box brain transcription factor 2
TGF-βtransforming growth factor-β
TREXtransiently expression of lncRNAs
Trincr1TRIM71 interacting long noncoding RNA 1
TUNATcl1 upstream neuron-associated lincRNA
UCA1urothelial carcinoma associated 1
Wdr5WD repeat domain 5
ZEB1/2Zincfinger E-box binding homeobox ½

References

  1. 1. Briggs JA, Wolvetang EJ, Mattick JS, Rinn JL, Barry G. Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron. 2015;88(5):861-877. DOI: 10.1016/j.neuron.2015.09.045
  2. 2. Knauss JL, Sun T. Regulatory mechanisms of long noncoding RNAs in vertebrate central nervous system development and function. Neuroscience. 2013;235:200-214. DOI: 10.1016/j.neuroscience.2013.01.022. Epub 2013 Jan 18
  3. 3. Quan Z, Zheng D, Qing H. Regulatory roles of long non-coding RNAs in the central nervous system and associated neurodegenerative diseases. Frontiers in Cellular Neuroscience. 2017;11:175. DOI: 10.3389/fncel.2017.00175
  4. 4. Salvatori B, Biscarini S, Morlando M. Non-coding RNAs in nervous system development and disease. Frontiers in Cell and Development Biology. 2020;8:273. DOI: 10.3389/fcell.2020.00273
  5. 5. Field AR, Jacobs FMJ, Fiddes IT, Phillips APR, Reyes-Ortiz AM, LaMontagne E, et al. Structurally conserved primate LncRNAs are transiently expressed during human cortical differentiation and influence cell-type-specific genes. Stem Cell Reports. 2019;12(2):245-257. DOI: 10.1016/j.stemcr.2018.12.006. Epub 2019 Jan 10
  6. 6. Lachmann A, Torre D, Keenan AB, Jagodnik KM, Lee HJ, Wang L, et al. Massive mining of publicly available RNA-seq data from human and mouse. Nature Communications. 2018;9(1):1366. DOI: 10.1038/s41467-018-03751-6
  7. 7. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(16):6062-6067. DOI: 10.1073/pnas.0400782101. Epub 2004 Apr 9
  8. 8. Liu SJ, Nowakowski TJ, Pollen AA, Lui JH, Horlbeck MA, Attenello FJ, et al. Single-cell analysis of long non-coding RNAs in the developing human neocortex. Genome Biology. 2016;17:67
  9. 9. Singh N. Role of mammalian long non-coding RNAs in normal and neuro oncological disorders. Genomics. 2021;113(5):3250-3273. DOI: 10.1016/j.ygeno.2021.07.015. Epub 2021 Jul 21
  10. 10. Sauer FC. Mitosis in the neural tube. The Journal of Comparative Neurology. 1935;62:377-405
  11. 11. Fujita S. Application of light and electron microscopy to the study of the cytogenesis of the forebrain. In: Hassler R, Stephen H, editors. Evolution of the Forebrain. New York: Plenum; 1966. pp. 180-196
  12. 12. Jacobson M. Cessation of DNA synthesis in retinal ganglion cells correlated with the time of specification of their central connections. Developmental Biology. 1968;17:219-232
  13. 13. Chenn A, McConnell SK. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell. 1995;82:631-641
  14. 14. Letourneau PC. Regulation of neuronal morphogenesis by cell-substratum adhesion. Soc. Neurosci. Symp. 1977;2:67-81
  15. 15. Jacobson M. Developmental Neurobiology. 2nd ed. New York: Plenum; 1991
  16. 16. Wallace VA. Purkinje cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Current Biology. 1999;9:445-448
  17. 17. Hatten ME. Riding the glial monorail: A common mechanism for glial-guided neuronal migration in different regions of the mammalian brain. Trends in Neurosciences. 1990;13:179-184
  18. 18. Rakic P. Mode of cell migration to superficial layers of fetal monkey neocortex. The Journal of Comparative Neurology. 1972;145:61-84
  19. 19. Rakic P, Sidman RL. Organization of cerebellar cortex secondary to deficit of granule cells in weaver mutant mice. The Journal of Comparative Neurology. 1973;152:133-162
  20. 20. Rakic P. Cell migration and neuronal ectopias in the brain. In: Bergsma D, editor. Morphogenesis and Malformations of Face and Brain, Birth Defects Original Article Series. Vol. 11(7). New York: Alan R. Liss; 1975. pp. 95-129
  21. 21. Komuro H, Rakic P. Selective role of N-type calcium channels in neuronal migration. Science. 1992;157:806-809
  22. 22. Edmondson JC, Liem RKH, Kuster JC, Hatten ME. Astrotactin: A novel neuronal cell surface antigen that mediates neuronal-astroglial interactions in cerebellar microcultures. The Journal of Cell Biology. 1988;106:505-517
  23. 23. Fishell G, Hatten ME. Astrotactin provides a receptor system for glia-guided neuronal migration. Development. 1991;113:755-765
  24. 24. Rakic P. Neurons in rhesus visual cortex: Systematic relation between time of origin and eventual disposition. Science. 1974;183:425-427
  25. 25. Walsh C, Cepko CL. Clonally related cortical cells show several migration patterns. Science. 1988;241:1342-1345
  26. 26. Frantz GD, McConnell SK. Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron. 1996;17:55-61
  27. 27. O'Rourke NA, Dailey ME, Smith SJ, McConnell SK. Diverse migratory pathways in the developing cerebral cortex. Science. 1992;258:299-302
  28. 28. Walsh C, Cepko CL. Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science. 1992;255:434-440
  29. 29. Matsunami H, Takeichi M. Fetal brain subdivisions defined by T- and E- cadherins expressions: Evidence for the role of cadherin activity in region-specific, cell-cell adhesion. Developmental Biology. 1995;172:466-478
  30. 30. Ramos AD, Andersen RE, Liu SJ, Nowakowski TJ, Hong SJ, Gertz C, et al. The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell. 2015;16:439-447
  31. 31. Fawal MA, Davy A. Impact of metabolic pathways and epigenetics on neural stem cells. Epigenet Insights. 2018;11:2516865718820946
  32. 32. Morizur L, Chicheportiche A, Gauthier LR, Daynac M, Boussin FD, Mouthon MA. Distinct molecular signatures of quiescent and activated adult neural stem cells reveal specific interactions with their microenvironment. Stem Cell Reports. 2018;11:565-577
  33. 33. Ming GL, Song H. Adult neurogenesis in the mammalian brain: Significant answers and significant questions. Neuron. 2011;70:687-702
  34. 34. Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nature Reviews. Neuroscience. 2006;7:179-193
  35. 35. Brill MS, Ninkovic J, Winpenny E, Hodge RD, Ozen I, Yang R, et al. Adult generation of glutamatergic olfactory bulb interneurons. Nature Neuroscience. 2009;12:1524-1533
  36. 36. Bonaguidi MA, Wheeler MA, Shapiro JS, Stadel RP, Sun GJ, Ming GL, et al. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell. 2011;145:1142-1155
  37. 37. Suh H, Consiglio A, Ray J, Sawai T, D’Amour KA, Gage FH. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell. 2007;1:515-528
  38. 38. Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M, et al. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell. 2010;6:445-456
  39. 39. Hodge RD, Kowalczyk TD, Wolf SA, Encinas JM, Rippey C, Enikolopov G, et al. Intermediate progenitors in adult hippocampal neurogenesis: Tbr2 expression and coordinate regulation of neuronal output. The Journal of Neuroscience. 2008;28:3707-3717
  40. 40. Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell. 2011;8:566-579
  41. 41. Zhu X, Hill RA, Dietrich D, Komitova M, Suzuki R, Nishiyama A. Age-dependent fate and lineage restriction of single NG2 cells. Development. 2011;138:745-753
  42. 42. Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A. Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. The Journal of Comparative Neurology. 2004;478:359-378
  43. 43. Bonaguidi MA, Song J, Ming GL, Song H. A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus. Current Opinion in Neurobiology. 2012;22:754-761
  44. 44. Liu SJ, Horlbeck MA, Cho SW, Birk HS, Malatesta M, He D, et al. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science. 2017;355(6320):aah7111. DOI: 10.1126/science.aah7111. Epub 2016 Dec 15
  45. 45. Hansen DV, Lui JH, Flandin P, Yoshikawa K, Rubenstein JL, Alvarez-Buylla A, et al. Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences. Nature Neuroscience. 2013;16:1576-1587
  46. 46. Rakic S, Zecevic N. Emerging complexity of layer I in human cerebral cortex. Cerebral Cortex. 2003;13:1072-1083
  47. 47. Ayana R, Singh S, Pati S. Decoding crucial LncRNAs implicated in neurogenesis and neurological disorders. Stem Cells and Development. 2017;26:541-553
  48. 48. Yao B, Jin P. Unlocking epigenetic codes in neurogenesis. Genes & Development. 2014;28:1253-1271
  49. 49. Goff LA, Groff AF, Sauvageau M, Trayes-Gibson Z, Sanchez-Gomez DB, Morse M, et al. Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain. Proceedings of the National Academy of Sciences of the United States of America. 2015;112:6855-6862
  50. 50. McCorkindale AL, Wahle P, Werner S, Jungreis I, Menzel P, Shukla CJ, et al. A gene expression atlas of embryonic neurogenesis in Drosophila reveals complex spatiotemporal regulation of lncRNAs. Development. 2019;146:dev175265
  51. 51. Lewitus E, Huttner WB. Neurodevelopmental LincRNA microsyteny conservation and mammalian brain size evolution. PLoS One. 2015;10:e0131818
  52. 52. Prajapati B, Fatma M, Maddhesiya P, Sodhi MK, Fatima M, Dargar T, et al. Identification and epigenetic analysis of divergent long non-coding RNAs in multilineage differentiation of human neural progenitor cells. RNA Biology. 2019;16:13-24
  53. 53. Wang L, Deng Y, Duan D, Sun S, Ge L, Zhuo Y, et al. Hyperthermia influences fate determination of neural stem cells with lncRNAs alterations in the early differentiation. PLoS One. 2017;12:e0171359
  54. 54. Zheng J, Yi D, Liu Y, Wang M, Zhu Y, Shi H. Long nonding RNA UCA1 regulates neural stem cell differentiation by controlling miR-1/Hes1 expression. American Journal of Translational Research. 2017;9:3696-3704
  55. 55. Knauss JL, Miao N, Kim SN, Nie Y, Shi Y, Wu T, et al. Long noncoding RNA Sox2ot and transcription factor YY1 co-regulate the differentiation of cortical neural progenitors by repressing Sox2. Cell Death & Disease. 2018;9:799
  56. 56. Ng SY, Bogu GK, Soh BS, Stanton LW. The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Molecular Cell. 2013;51:349-359
  57. 57. Li W, Shen W, Zhang B, Tian K, Li Y, Mu L, et al. Long noncoding RNA LncKdm2b regulates cortical neuronal differentiation by cis-activating Kdm2b. Protein & Cell. 2020;11(3):161-186
  58. 58. Pavlaki I, Alammari F, Sun B, Clark N, Sirey T, Lee S, et al. The long non-coding RNA Paupar promotes KAP1-dependent chromatin changes and regulates olfactory bulb neurogenesis. The EMBO Journal. 2018;37(10):e98219
  59. 59. Vance KW, Sansom SN, Lee S, Chalei V, Kong L, Cooper SE, et al. The long non-coding RNA Paupar regulates the expression of both local and distal genes. The EMBO Journal. 2014;33:296-311
  60. 60. Cheng X, Li H, Zhao H, Li W, Qin J, Jin G. Function and mechanism of long non-coding RNA Gm21284 in the development of hippocampal cholinergic neurons. Cell & Bioscience. 2019;9:72
  61. 61. Weng R, Lu C, Liu X, Li G, Lan Y, Qiao J, et al. Long noncoding RNA-1604 orchestrates neural differentiation through the miR-200c/ZEB axis. Stem Cells. 2018;36:325-336
  62. 62. Zhang L, Xue Z, Yan J, Wang J, Liu Q , Jiang H. LncRNA Riken-201 and Riken-203 modulates neural development by regulating the Sox6 through sequestering miRNAs. Cell Proliferation. 2019a;52:e12573
  63. 63. Zhang L, Yan J, Liu Q , Xie Z, Jiang H. LncRNA Rik-203 contributes to anesthesia neurotoxicity via microRNA-101a-3p and GSK-3beta-mediated neural differentiation. Scientific Reports. 2019;9:6822
  64. 64. Gao Y, Zhang R, Wei G, Dai S, Zhang X, Yang W, et al. Long noncoding RNA maternally expressed 3 increases the expression of neuronspecific genes by targeting miR-128-3p in all-trans retinoic acid-induced neurogenic differentiation from amniotic epithelial cells. Frontiers in Cell and Development Biology. 2019;7:342
  65. 65. Chen L, Feng P, Zhu X, He S, Duan J, Zhou D. Long non-coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells. Journal of Cellular and Molecular Medicine. 2016;20:2102-2110
  66. 66. Grammatikakis I, Gorospe M. Identification of neural stem cell differentiation repressor complex Pnky-PTBP1. Stem Cell Investigation. 2016;3:10
  67. 67. Winzi M, Casas Vila N, Paszkowski-Rogacz M, Ding L, Noack S, Theis M, et al. The long noncoding RNA lncR492 inhibits neural differentiation of murine embryonic stem cells. PLoS One. 2018;13:e0191682
  68. 68. Zheng X, Lin C, Li Y, Ye J, Zhou J, Guo P. Long noncoding RNA BDNF-AS regulates ketamine-induced neurotoxicity in neural stem cell derived neurons. Biomedicine & Pharmacotherapy. 2016;82:722-728
  69. 69. Dong X, Chen K, Cuevas-Diaz Duran R, You Y, Sloan SA, Zhang Y, et al. Comprehensive identification of long non-coding RNAs in purified cell types from the brain reveals functional LncRNA in OPC fate determination. PLoS Genetics. 2015;11:e1005669
  70. 70. He D, Wang J, Lu Y, Deng Y, Zhao C, Xu L, et al. lncRNA functional networks in oligodendrocytes reveal stage-specific myelination control by an lncOL1/Suz12 complex in the CNS. Neuron. 2017;93:362-378
  71. 71. Li Y, Guo B, Yang R, Xiao Z, Gao X, Yu J, et al. A novel long noncoding RNA lnc158 promotes the differentiation of mouse neural precursor cells into oligodendrocytes by targeting nuclear factor-IB. Neuroreport. 2018;29:1121-1128
  72. 72. Kasuga Y, Fudge AD, Zhang Y, Li H. Characterization of a long noncoding RNA Pcdh17it as a novel marker for immature premyelinating oligodendrocytes. Glia. 2019;67:2166-2177
  73. 73. Mills JD, Kavanagh T, Kim WS, Chen BJ, Waters PD, Halliday GM, et al. High expression of long intervening non-coding RNA OLMALINC in the human cortical white matter is associated with regulation of oligodendrocyte maturation. Molecular Brain. 2015;8:2
  74. 74. Wang F, Wang Q , Liu B, Mei L, Ma S, Wang S, et al. The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum. Cell Death and Differentiation. 2021;28(9):2634-2650. DOI: 10.1038/s41418-021-00774-3. Epub 2021 Mar 24
  75. 75. Raveendra BL, Swarnkar S, Avchalumov Y, Liu X-A, Grinman E, Badal K, et al. Long noncoding RNA GM12371 acts as a transcriptional regulator of synapse function. Proceedings of the National Academy of Sciences. 2018;115:E10197
  76. 76. Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS. Specific expression of long noncoding RNAs in the mouse brain. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:716-721
  77. 77. Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011;477:295-300
  78. 78. Li YP, Duan FF, Zhao YT, Gu KL, Liao LQ , Su HB, et al. A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells. Nature Communications. 2019;10:1368
  79. 79. Askarian-Amiri ME, Seyfoddin V, Smart CE, Wang J, Kim JE, Hansji H, et al. Emerging role of long non-coding RNA SOX2OT in SOX2 regulation in breast cancer. PLoS One. 2014;9:e102140
  80. 80. Kan L, Israsena N, Zhang Z, Hu M, Zhao LR, Jalali A, et al. Sox1 acts through multiple independent pathways to promote neurogenesis. Developmental Biology. 2004;269(2):580-594. DOI: 10.1016/j.ydbio.2004.02.005
  81. 81. Zhang S, Cui W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World Journal of Stem Cells. 2014;6:305-311
  82. 82. Ahmad A, Strohbuecker S, Tufarelli C, Sottile V. Expression of a SOX1 overlapping transcript in neural differentiation and cancer models. Cellular and Molecular Life Sciences. 2017;74:4245-4258
  83. 83. Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344-352
  84. 84. Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annual Review of Neuroscience. 2009;32:149-184. DOI: 10.1146/annurev.neuro.051508.135600
  85. 85. Benito-Muñoz M, Matute C, Cavaliere F. Adenosine A1 receptor inhibits postnatal neurogenesis and sustains astrogliogenesis from the subventricular zone. Glia. 2016;64(9):1465-1478. DOI: 10.1002/glia.23010. Epub 2016 Jun 15
  86. 86. Ohtsuka T, Shimojo H, Matsunaga M, Watanabe N, Kometani K, Minato N, et al. Gene expression profiling of neural stem cells and identification of regulators of neural differentiation during cortical development. Stem Cells. 2011;29(11):1817-1828. DOI: 10.1002/stem.731
  87. 87. Lein ES, Belgard TG, Hawrylycz M, Molnár Z. Transcriptomic perspectives on neocortical structure, development, evolution, and disease. Annual Review of Neuroscience. 2017;40:629-652. DOI: 10.1146/annurev-neuro-070815-013858. Epub 2017 Jun 29
  88. 88. Emery B, Lu QR. Transcriptional and epigenetic regulation of oligodendrocyte development and myelination in the central nervous system. Cold Spring Harbor Perspectives in Biology. 2015;7:a020461
  89. 89. Zuchero JB, Barres BA. Intrinsic and extrinsic control of oligodendrocyte development. Current Opinion in Neurobiology. 2013;23:914-920

Written By

Neetu Singh

Submitted: 29 April 2022 Reviewed: 25 August 2022 Published: 10 October 2022