Most of legume plants produce
The nodule symbiosis with rhizobia is a unique feature of legumes among land plants. The infection processes are regulated by interaction with rhizobia. Nodulation factors (Nod factors) that are lipochitin oligosaccharides secreted by rhizobia trigger the symbiotic responses [3,4]. LysM containing receptor proteins, NFR1 and NFR5 in
Although the root nodule symbiosis is beneficial to host plants, excessive nodulation interferes with plant growth, probably, due to a high energy cost against the nitrogen fixation. Therefore, legumes have developed negative feedback pathways that optimize total nodule number and mass in a single plant. A major pathway that regulates nodule number is known as autoregulation of nodulation (AON) [20,21], which is activated by nodulation, and systemically prevents subsequent formation of nodules through root-shoot communications. This systemic effect has been demonstrated by split root experiments. Infection with rhizobia to one part of the root results in reduction in the nodule number in the other part of the root that was inoculated 3-4 days after the first inoculation procedure [20,22]. Reciprocal grafting experiments with mutants defective in AON have further shown that the inhibitory effect seen in the root is mediated by the shoot [23-27]. Two types of long-distance signals that are derived from either the root or shoot have been postulated in AON to explain the root-shoot communication; The root-derived signal that was generated by early nodulation signaling is translocated to the shoot, and activates shoot-acting AON factors to produce the shoot-derived inhibitor (SDI), which, in turn, is transported down to the root, and inhibits nodulation through root-acting AON factors.
In the past decade, many mutants exhibiting impaired nodulation have been isolated, and genes responsible for symbiotic phenotypes have been identified. The accumulating lines of evidence led to basic models for the nodulation signaling pathway. Factors involved in AON have been identified from several legume species. Our knowledge of AON has greatly advanced at molecular levels by efforts of many researchers, although many pieces have remained to understand how AON systemically regulates nodulation. In this review, we highlight past work in this area and describe recent results obtained with forward and reverse genetic approaches as well as with biochemical works, along the basic scheme of AON that has been depicted by pioneer works.
2. Shoot factors involved in AON
Genetic screens have identified loci that affect AON in several legume species. These mutants often display excessive nodules within an enhanced nodulation zone in either the presence of or the absence of nitrate, which possesses inhibitory effects on nodulation (see below). This phenotype is termed hypernodulation or supernodulation . Soybean
Positional cloning of genes responsible for the hypernodulation phenotype revealed that AON has diverted factors involved in the shoot apical meristem homeostasis as shoot-acting factors. The causative genes of these mutants encode leucine-rich repeat (LRR) containing receptor protein kinases orthologous to each other [25,26,30,31]. It is expected that ligand-receptor interaction in the shoot regulates nodulation in the root.
3. Root-derived CLE peptides
In the shoot meristem regulation, CLV1 restricts meristem sizes through interaction with CLV3 that is a member of CLE (CLV3/ESR-related) small secreted peptide family [42-44]. CLV3 peptide is produced from its primary translational product by proteolytic processing . By analogy to the CLV1-CLV3 pathway, the shoot-acting AON receptor protein kinases were expected to recognize CLE peptides that might act as the root-derived signal. Okamoto et al. have comprehensively analyzed expression of genes that encode CLE-peptide precursors in
Okamoto et al. have determined the structure of the mature CLE-RS2 . This peptide is composed of 13 amino-acid residues corresponding to the conserved C-terminal CLE domain of its precursor, and the seventh proline residue is hydroxylated, and further posttranslationally modified with three residues of arabinose. This proline residue is conserved in all putative CLE peptides that are encoded by genes whose ectopic expression suppresses nodulation. The same arabinosylation has been also found at the seventh hydroxyproline residue of the CLV3 peptide. This modified CLV3 peptide interacts more strongly with the ectodomain of CLV1 . The synthetic arabinosylated CLE-RS1 and CLE-RS2 bound to HAR1 protein, but not to a loss-of-function HAR1 derivative with an amino acid substitution at a residue critical for ligand binding of the CLV1 family receptor kinases in Arabidopsis [52,54]. The activity of the CLE-RS1 and CLE-RS2 peptides to suppress nodulation has been demonstrated by feeding experiments with the synthetic arabinosylated peptides . The synthetic CLE-RS2 and CLE-RS1 peptides that were fed from cotyledon surfaces suppressed nodulation depending on
Unlike the short-distance communication between CLV1 and CLV3 (these genes express in restricted region of the shoot apical meristem), long-ranged transport is necessary for the root-derived CLE peptides to interact with HAR1. The xylem often mediates the transport of molecules from the root to the shoot . The arabinosylated CLE-RS2 was detected in xylem sap collected from soybean shoots whose roots have been transformed to express
4. Expression of
CLE genes that encode the root-derived signal
Transcriptional regulation of the root-derived signal is an important step to regulate AON. The expression in response to rhizobial infection is mediated by the early signaling pathway required for nodulation processes . Transcription factors that are involved in the early nodulation signaling, such as NSP1, NSP2, and NIN, are required for expression of
In addition to rhizobial infection, expression of
5. Shoot-derived inhibitors
The SDI is thought to be produced depending on activation of the shoot-acting receptor protein kinases. Expression of
Although the shoot-derived molecule that acts as the SDI has not yet been identified, several phytohormones have shown inhibitory effects on nodulation  and associated with AON. Auxin has been postulated to be involved in nodulation , and is transported from the shoot to the root by cell-to-cell transport mediated by auxin carriers, and also thought to travel in the phloem.
In soybean, on the other hand, it has been reported that metabolic pathways of jasmonic acid in the shoot are altered by
6. Root-acting factors involved in inhibition of nodulation
According to the scenario described above, the mature CLE peptides whose genes express in response to rhizobial infection act as the root-derived signals, and activate shoot-acting receptor protein kinases including HAR1 and KLV to generate the SDI, which in turn inhibits nodulation. Root-acting AON factors involved in production of the root-derived signal or perception of the SDI are required for AON to exert the inhibitory effect. Root-specific hypernodulation mutants, pea
Contrary to NOD3/MtRND1,
7. Which steps of nodulation are influenced by AON?
Although molecular mechanisms, by which nodule formation is suppressed in the root, have been largely unknown, several results may be able to speculate how AON influences nodulation. Rhizobia usually infect at the root tip region where elongation of root hairs occurs, and nodule formation is initiated at the infection site. Then, nodule formation at the root region that is developmentally younger than the first inoculated region is suppressed. Thereby, nodule formation is limited at the first inoculation zone of the root. The mutants exhibiting impaired AON show increases in number of both infection threads and nodules. Nodule formation in these mutants is deregulated with respect of the nodule density and the region that form nodules. It is suggested that AON influences on early stages of rhizobial infection and local regulation of nodule number. Identification of loss-of-function mutants of a
Saur et al. have shown a strong reduction of
In the shoot apical meristem homeostasis, the CLV1-CLV3 pathway represses a gene encoding a homeobox transcription factor, WUSCHEL, which directly activates
Forward genetic analyses have greatly contributed to identify novel factors that are involved in AON. The series of investigations revealed that AON has diverted factors required for the homeostasis of the shoot apical meristem as the shoot-acting factors. The ligand-receptor relationship between HAR1 and the root-derived CLE peptides has been clearly demonstrated by the reverse genetic approaches and biochemical assays. The similarity of AON to the CLV1-CLV3 pathway suggests that AON may have recruited functions from pathways that generally work in non-leguminous species. How legumes have been molecularly specialized from non-leguminous species is an important question to understand molecular basis on the root nodule symbiosis. Studies on AON would shed light on this fundamental question besides elucidation of the molecular nature of the systemic inhibitory pathway. There remains three major questions to to elucidate AON at molecular levels: (1) How expression of the root-derived signals is regulated, (2) What is a bona-field SDI, (3) Molecular mechanisms, by which nodulation is suppressed in the root. Lin et al. have shown the SDI activity in aqueous extracts prepared from leaves of inoculated wild type soybean. Forward genetics has identified TML as the root-acting AON factor involved in suppression of nodulation downstream of the SDI. These findings as well as data obtained by efforts of many researchers would be clues to resolve these questions.
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