1. Introduction
A fundamental question in biology is how communication and exchange of short-range signals shape the microenvironment for setting up functional tissues. In all adult tissues and organs harboring stem cells, tissue homeostasis and repair relies on the proper communication of stem cells and their differentiating daughter cells with the local tissue microenvironment that homes them [1, 2]. Stem cell research has made outstanding contributions on the factors that maintain stem cells or drive them to generate differentiated daughter cells. The use of stem cells in the development of cell-based medicine and in repairing malformed, damaged or aging tissues demands a better understanding of stem cells at a molecular level and of how they behave in their physiological context.
The basic principles controlling stem cell self-renewal versus differentiation are strikingly conserved during evolution and their regulatory logic is often very similar among homologous stem cell niches. Since the signaling pathways and their regulatory circuits are highly complex in the mammalian system with significant molecular redundancy, they are often difficult to study. Therefore, using a simpler model system such as the
The
The proposed chapter gives an overview of the
2. The Drosophila testis
Organogenesis of the
The first signs of testis organogenesis are detected in 1st instar larvae (L1) and a testis with a mature stem cell niche and all premeiotic stages is detected at 3rd instar larvae (L3). The
Testis organogenesis is completed during pupal stages. For the formation of a mature testis and a functional reproductive tract, the
2.1. Cyst cells: The safeguards of the Germline
Critical for testis differentiation and morphogenesis is the cyst microenvironment created by the cyst cells (CySCs and SCCs) that enclose the germline cells, accompany them throughout their differentiation steps up to sperm individualization and maintain cyst integrity and architecture [22, 23]. Although it is well established that soma-germline physical contact is critical for the cell communication and for promoting their mutual development and differentiation [3], it remains so far elusive how these tightly packed cysts coordinate adhesion and cell shape changes with signaling and membrane addition on a mechanistic level.
The thin and squamous cyst cells lack the columnar epithelial structure of e.g. the ovarian follicular epithelium, which caught the attention of scientists analyzing apico-basal polarity many years ago. For this reason, several questions concerning cyst cell architecture, apical-basal polarity and sub-cellular localization of cytoskeletal proteins such as Dlg, Integrin and Talin remained unclear. Preliminary data show that cyst cells are polarized with an inner-apical surface phasing the germline (Fig. 2E; arrowheads) [22] and an outer-basal surface surrounded by ECM [18]. Critical cytoskeletal and polarity components localize at cyst cells, such as Rho1, Bazooka (Baz), Fasciclin II (FasII), Integrin-linked kinase (ILK), βPS-Integrin (encoded by the
So far the main evidence for cyst cell (CySCs and SCCs) function came from the analysis of individual signal transduction pathways that establish a cross talk between the soma and the germline. In this chapter recent findings critically affecting germline-soma communication and coordination will be highlighted, with emphasis on the role of cytoskeletal and scaffolding components such as integrins and adaptor proteins, ECM and the septate junction components. Interestingly, the
2.2. Niche Homeostasis: Signaling regulation of stemness vs. differentiation
Tissue specific stem cells are the lifetime source of many types of differentiated cells. They reside in microenvironments, the stem cells niches that have an important role in stem cell behavior [28]. Gamete development requires a coordinated soma-germ line interaction that keeps the balance between germline stem cell renewal and differentiation. The balance between stem cell identity and differentiation at the
Interestingly, very recent findings revealed that the Hedgehog (Hh) ligand secreted from the hub cells activates the Hh signaling in CySCs (and not in the GSCs) with critical function in CySC maintenance [37-40]. Hh overexpression leads in increased number of CySCs, identified as Zfh-1 positive cyst cells outside the niche, which can still proliferate in contrast to the normal post-mitotic SCCs. Furthermore, rescue of STAT depleted testis by Hh signaling activation in the CySCs can rescue the CySCs but GSC and germline maintenance is still impaired, as these Zfh-1 positive CySCs are not able to induce the GSC over-proliferation phenotype observed in SCCs ectopic Zfh-1 activation [38]. This suggests that [1]
Notably, BMP seems to be the primary pathway leading to GSC self-renewal in the
Critical for germ cell differentiation is the expression of
Another signaling pathway restricting GSC proliferation is mediated by Epidermal Growth Factor Receptor (EGFR), whose inactivation in SCCs leads to an expansion of male GSCs [50]. In
3. The male stem cell niche: Specification and positioning
The somatic cells of the hub form the organizing center, a cluster of non-dividing cells, at the anterior part of the embryonic male gonad originating, as already discussed, from SGPs [10]. However, not only the hub but also the cyst cells are specified from the SGPs and the common origin between hub and CySCs has been shown by lineage tracing experiments [57]. This is further supported by the fact that both cell types can be traced using the same cell markers such as Zfh-1 and Traffic Jam (TJ) [25]. Hub cell fate vs. cyst cell fate is specified prior to gonad coalesce in a subset of somatic gonadal precursor cells (SGPs) upon Notch signaling activation [57]. In a next step, the
We have discussed how the posteriorly expressed Hox genes
3.1. Some function, different mechanisms: How the Boss/Sev-AbdB cross-talk regulates niche positioning and integrity
As already mentioned, the Boss/Sev signaling pathway plays an important role in hub positioning in the
Taken together these studies show that the same players, AbdB, Boss, Sev and Integrin, are used in larval stages to preserve hub positioning and integrity after the initial establishment at embryonic stages but using a slightly variable mechanism: (a) In embryonic gonads,
3.1.1. Boss mediates, in a Dynamin-and Src-dependent way, germline-soma signaling in larval testis
In order to elucidate how the Hox transcription factor Abd-B affects Boss localization, genes directly regulated by Abd-B in the
4. Dlg, Scrib & Lgl: New functions in the Drosophila testis
The
Dlg belongs to the MAGUK (membrane-associated guanylate kinases) protein family, a class of scaffolding proteins that recruit signaling molecules into localized multimolecular complexes [83, 91]. Dlg localizes at the cytoplasmic side of septate junctions between adjacent epithelial cells (the equivalent of vertebrate tight junctions), as well as in neuromuscular junctions (NMJs). It contains three PDZ domains involved in protein-protein interactions with membrane or cytoskeletal proteins, an SH3 domain and a GUK domain. Scrib is also a septate junctional protein of the LAP protein family, containing four PDZ domains and leucine-rich repeats (LRRs) [85, 87, 91, 92]. Lgl is a cytosolic protein containing two WD40 motifs, involved in protein-protein interactions [87]. Lgl can bind to non-muscle myosin II and to the cytoskeleton matrix, along the baso-lateral portion of the plasma membrane of epithelial cells to affect cell polarization [93]. All three proteins, often referred to as the Dlg-polarity module, are highly conserved in sequence among different species and growing evidence suggests that they are functionally conserved to a large degree since the vertebrate homologues can rescue the polarity defects and tumorous overgrowth of the respective
4.1. Dlg, Scrib & Lgl: Multitasking proteins in common pathways in various tissues
Research over several years, defined
4.1.1. Polarity establishment in various cellular contexts
The Dlg polarity module works in cooperation with the Crumbs-(Crb, Pals1 & Patj) and the Par-(Bazooka/Par3, Par6, αPKC) polarity complexes to control polarity in several tissues. In epithelial cells, polarity is established in a finely balanced process involving cooperative and antagonistic interactions among the apical Par-and Crumbs-complexes and the basolateral Dlg-complex, which restrict the activity of each complex to its specific membrane domain [85, 86]. In neuroblast asymmetric cell division Dlg, Scrib and Lgl cooperate with the Par and Inscutable-Pins complexes whereas microtubules induce Pins & Gαi cortical polarity through Dlg and Khc-73 interactions [86, 105, 106]. In the
4.1.2. Vesicle and membrane trafficking
Several pieces of evidence suggest that Dlg, Scrib and Lgl are involved in vesicle and membrane trafficking [86, 102]: i) Dlg and Strabismus (VanGogh) form a complex that allows membrane deposition during cellularization in
4.1.3. Gene regulation and signaling output
Recent studies associate Dlg, Scrib and Lgl with transcriptional response and signaling output since they can regulate the shuttling of critical components between junctional complexes and the nucleus. Such a shuttling mechanism has been described for the Dlg and Scrib vertebrate homologues [116, 117]. In
Taken together, Dlg, Scrib and Lgl emerge as dynamic cytoskeletal components which affect polarity, cell structure and behavior by directing the trafficking of proteins to proper plasma membrane surfaces of the cell, and by organizing and stabilizing supramolecular adhesion and signaling complexes through their action as scaffolding adaptor molecules [83-86, 89-91, 109, 111].
4.2. Dlg, Scrib & Lgl in testis somatic cells promote cyst cell function & testis homeostasis
Septate junctions are primary candidates for cyst integrity and coordination, as apart from acting as sealing junctions in epithelia and neurons by mediating cell-cell adhesion, they act as scaffolding networks together with multiple pathways to promote organ morphogenesis [120]. Although the function of Dlg, Scrib and Lgl as TSGs has been intensively studied, their role in testis development has been largely overlooked, as mutations in their coding genes do not result in testis tumors. Moreover, the fact that testes lack an easy to study columnar epithelium, which facilitates analysis of apicobasal polarity genes, didn’t favor the analysis of these genes in this stem cell system for many years. The last years a number of studies addressed the role of
As Dlg, Scrib and Lgl act cooperatively in several tissue contexts [23, 84], their function during male gonad and testis development was analyzed in a comparable way [22, 119]. This work revealed that cell autonomous
Another striking finding was the formation of wavy and ruffled plasma membrane upon
Another way to interpret this result would be to consider that Dlg regulates the intensity of germ cell encapsulation through the Egfr pathway, which is the major signaling pathway active at the microenvironment of the spermatogonial cysts [50, 51]. Membrane ruffling, detected in somatic cells upon
5. Conclusions and future perspectives
Cell polarity and signaling are fundamental biological processes that impact stem cell function, cancer, cell migration, tissue morphogenesis and response to pathogenic infections. Growing scientific evidence suggests that these processes are intimately linked. Moreover, shuttling of signaling complexes into specific intracellular regions happens via their recruitment in sub-cellular domains guided by polarity scaffolds. The microenvironment of the male testis cysts, built by the cyst cell-germline intimate connection, provides an ideal model system to investigate how soma-germline adhesion and cell morphological changes are coordinated with cell communication and exchange of short-range signals.
So far the main evidence for cyst cell (CySCs and SCCs) function came from the analysis of individual signal transduction pathways that establish a cross-talk between the soma and the germline. Now we know that cyst cells are crucially important for soma-germline cyst integrity, overall rigidity and for setting up a functional cyst microenvironment. To this end, it is important (a) to investigate the requirement of the somatic lineage, the cyst cells, as safeguard of germline function, and (b) to characterize the local soma-germline communication within the cysts with focus on how polarity scaffolds and signaling platforms promote this. Resolving the basic features of cyst’s microenvironment and soma-germline coordination will allow the study of more complex questions in the future such as long-range signaling at the level of cyst-cyst communication. Moreover, the use of a combination of genetic, genomic and high-resolution microscopy techniques to approach these questions will enable us to adapt tools, already successfully established in other tissues and model systems (such as FRAP, FRET and organ cultures) to the
Acknowledgments
The author wishes to thank the
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