CLAVATA-WUSCHEL negative feedback loop in shoot apical meristem stem-cell homeostasis

The size of the stem-cell pool in the shoot apical meristem is held steady by a two-cell-layer negative feedback loop. The homeodomain transcription factor WUSCHEL (WUS) is made in the organizing center (OC), moves through plasmodesmata into the overlying central zone, and there both specifies stem-cell fate and directly activates CLAVATA3 (CLV3). CLV3 is processed and secreted as an arabinosylated 12/13-amino-acid CLE peptide. It is perceived at the plasma membrane of the underlying cells by parallel receptor systems: the LRR receptor kinase CLV1 and its paralogs BAM1/BAM2, which bind the peptide directly, and a heteromeric complex of the kinase-less LRR receptor-like protein CLV2 with the pseudokinase CORYNE (CRN). Whether CLV2/CRN binds the ligand directly is disputed; it acts at least as a co-receptor. Receptor signalling, relayed through CIK co-receptor kinases and PBL-type cytoplasmic kinases, represses WUS transcription and confines the OC. More stem cells therefore make more CLV3, which reduces WUS and so limits stem-cell number. When CLV1 is lost, BAM genes are de-repressed in the meristem centre and partly compensate. The KNOX homeodomain protein SHOOT MERISTEMLESS (STM), which keeps meristem cells undifferentiated and interacts genetically with the CLV genes, is shown only as optional context. RPK2, the CIK and PBL relay kinases, CLE processing, floral-meristem termination by AGAMOUS, and the root CLE40-ACR4 and CLE45-BAM3 pathways are outside this module boundary.

MODULE:shoot_meristem_clv_wus_feedbackDRAFTCONCRETESignaling Pathwaymodules/shoot_meristem_clv_wus_feedback.yaml
homeostasis of number of meristem cellsGO:0007639 stem cell population maintenanceGO:0019827
PMID:10761929
CLV genes repress WUS, and WUS induces the stem-cell marker CLV3, which forms a feedback loop between stem cells and the organizing center.
Our data suggest that the shoot meristem has properties of a self-regulatory system in which WUS/CLV interactions establish a feedback loop between the stem cells and the underlying organizing center.
PMID:21979915
WUS protein moves from the OC to the central zone, where it binds the CLV3 promoter and activates its transcription.
the WUS protein, after being synthesized in cells of the OC, migrates into the CZ, where it activates CLV3 transcription by binding to its promoter elements.
PMID:21705761
CLV1, CLV2 and CRN restrict WUS expression, and CLV1/BAM1 and CLV2/CRN act as parallel complexes in the shoot meristem.
Our results suggest a model in which CLV1/BAM1 and CLV2/CRN complexes act in separate, parallel pathways in shoot meristems
PMID:28355208
In clv1 mutants, CLV1-related BAM receptor kinases are expressed ectopically and buffer stem-cell proliferation.
in the absence of CLV1, CLV1-related receptor kinases are ectopically expressed but also buffer stem cell proliferation through the auto-repression of their own expression.

Member gene reviews: CLV1, CLV2, CRN and BAM1 were curated with this module. CLV3, WUS and STM reviews were used read-only. Annoton MFs match each gene review's core_functions. CLV1 and BAM1 use GO:0004675 (the CLV1 core MF was updated from GO:0004674). CLV2 uses coreceptor activity (GO:0015026) and CRN uses signaling receptor complex adaptor activity (GO:0030159). No production GO-CAM in gocams/index.tsv contains these Arabidopsis proteins. PANTHER family ids were not asserted.

7Nodes
4Parts
1Variant Sets
2Variants
7Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:shoot_meristem_clv_wus_feedback deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

7 gene-function check(s) reflected in core functions · 0 conflict(s) · 0 evidence or coverage gap(s) (7 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
wus_tf WUS
UniProtKB:Q9SB92
Gene 		DNA-binding transcription factor activity
GO:0003700 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
clv3_peptide CLV3
UniProtKB:Q9XF04
Gene 		receptor serine/threonine kinase binding
GO:0033612 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
clv1_receptor_kinase CLV1
UniProtKB:Q9SYQ8
Gene 		transmembrane receptor protein serine/threonine kinase activity
GO:0004675 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bam1_receptor_kinase BAM1
UniProtKB:O49545
Gene 		transmembrane receptor protein serine/threonine kinase activity
GO:0004675 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
clv2_coreceptor CLV2
UniProtKB:O80809
Gene 		coreceptor activity
GO:0015026 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
crn_pseudokinase_adaptor CRN
UniProtKB:Q9LYU7
Gene 		signaling receptor complex adaptor activity
GO:0030159 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
stm_tf STM
UniProtKB:Q38874
Gene 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • clv3_perception ⊣ wus_organizing_center [closed]
    clv3_perception is regulated by clv3_ligand: feedback loop closed

Gene-review completeness (7/7 grounded genes reviewed)

7 complete review(s) · 6 with deep research · 0 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
BAM1 O49545 ✓ ✓ ✗
CLV1 Q9SYQ8 ✓ ✓ ✓
CLV2 O80809 ✓ ✓ ✓
CLV3 Q9XF04 ✓ ✓ ✓
CRN Q9LYU7 ✓ ✓ ✓
STM Q38874 ✓ ✓ ✓
WUS Q9SB92 ✓ ✓ ✓

Details

Context
Arabidopsis thalianaNCBITaxon:3702
CLV-WUS stem-cell feedback loop (shoot apical meristem)Signaling Pathwayshoot_meristem_clv_wus_feedback
homeostasis of number of meristem cellsGO:0007639 stem cell population maintenanceGO:0019827
Context
Arabidopsis thalianaNCBITaxon:3702

Connections

wus_organizing_center -> clv3_ligand Positively Regulates
WUS protein moves into the central zone and activates CLV3 transcription.
PMID:21979915
WUS binds CLV3 promoter elements in the central zone.
migrates into the CZ, where it activates CLV3 transcription by binding to its promoter elements.
clv3_ligand -> clv3_perception Provides Input For
Secreted CLV3 peptide is the ligand sensed by the CLV1/BAM and CLV2/CRN receptor systems.
clv3_perception -> wus_organizing_center Negatively Regulates
CLV3 receptor signalling represses WUS transcription and confines the organizing center, which closes the negative feedback loop.
PMID:10761929
CLV genes repress WUS at the transcript level.
the CLV genes repress WUS at the transcript level
STM keeps the meristem undifferentiated, which provides the competent tissue in which the WUS-CLV3 loop operates. This is context, not a direct regulatory link.
Part 1: organizing-center transcription factor (positive arm)
WUS stem-cell-promoting transcription factorRegulatory Stepwus_organizing_center

WUS is transcribed in the organizing center. The protein moves into the central zone, where it maintains stem-cell identity and binds the CLV3 promoter to activate CLV3.

Annotons

WUS: homeodomain DNA-binding transcription factor
wus_tf
Participant: Gene Product: WUS
Gene Product:
WUSUniProtKB:Q9SB92

Function

DNA-binding transcription factor activityGO:0003700

Processes

stem cell population maintenanceGO:0019827

Locations

nucleusGO:0005634

Non-cell-autonomous stem-cell inducer. It activates CLV3, its own negative regulator.

PMID:21979915
WUS is made in the OC and activates CLV3 in the central zone.
WUS specifies stem cell fate and also restricts its own levels by activating a negative regulator, CLAVATA3 (CLV3), in adjacent cells of the central zone (CZ).
Part 2: stem-cell-derived peptide ligand
CLV3 CLE peptide signalRegulatory Stepclv3_ligand

CLV3 is expressed in central-zone stem cells and secreted into the apoplast as a processed, arabinosylated CLE peptide. It reports stem-cell number to the cells beneath.

Annotons

CLV3: secreted CLE peptide ligand of CLV1/BAM receptor kinases
clv3_peptide
Participant: Gene Product: CLV3
Gene Product:
CLV3UniProtKB:Q9XF04

Function

receptor serine/threonine kinase bindingGO:0033612 GO has no plant peptide-hormone activity term. This follows the CLV3 gene review, which describes the ligand-receptor kinase interaction.

Processes

regulation of meristem structural organizationGO:0009934

Locations

apoplastGO:0048046

Mobile negative-feedback signal from the stem cells.

PMID:10082464
CLV3 encodes a small extracellular protein that acts non-autonomously with CLV1 as a putative ligand-receptor pair.
These proteins may act as a ligand-receptor pair in a signal transduction pathway, coordinating growth between adjacent meristematic regions.
PMID:18202283
The CLV3 peptide binds the CLV1 ectodomain directly.
the CLV3 peptide directly binds the CLV1 ectodomain with a dissociation constant of 17.5 nM
Part 3: CLV3 perception at the plasma membrane
Parallel CLV3 receptor systemsSignaling Pathwayclv3_perception

Two receptor systems that act at the same time sense CLV3 at the plasma membrane of OC and rib-zone cells: CLV1-family receptor kinases (CLV1, BAM1, BAM2) and the CLV2/CRN complex. Either system alone gives partial repression of WUS. Loss of both (for example clv1 bam1 or clv1 clv2) strongly enlarges the meristem. CIK co-receptor kinases and PBL34/35/36 cytoplasmic kinases relay the signal and are outside this module boundary.

Variant set: CLV3 receptor systems by receptor architecture (ligand-binding receptor kinase versus kinase-less co-receptor complex) (One Or More)
PMID:20626648
CLV2/CRN and CLV1/BAM form two distinct receptor complexes.
In this study we find evidence for two distinct receptor complexes involved in stem cell regulation in Arabidopsis, CLV2/CRN and CLV1/BAM.

Both systems are present in the meristem and contribute additively, so this is not an either/or choice.

CLV1-family LRR receptor kinasesProtein Complexclv1_bam_receptor_kinases

CLV1 homomers and CLV1/BAM heteromers. Their LRR ectodomains bind CLV3 directly, and their kinase domains phosphorylate CIK and PBL substrates. In the wild type, BAM1 is mainly peripheral. It is up-regulated centrally in clv1 mutants, and clv1 bam1 double mutants have strongly enlarged meristems with expanded WUS.

Annotons

CLV1: CLV3 receptor kinase
clv1_receptor_kinase
Participant: Gene Product: CLV1
Gene Product:
CLV1UniProtKB:Q9SYQ8

Function

transmembrane receptor protein serine/threonine kinase activityGO:0004675

Processes

regulation of meristem structural organizationGO:0009934

Locations

plasma membraneGO:0005886

Primary high-affinity CLV3 receptor in the OC and rib zone.

PMID:18202283
CLV3 binds the CLV1 ectodomain directly.
the CLV3 peptide directly binds the CLV1 ectodomain with a dissociation constant of 17.5 nM
PMID:34935965
CLV1 and BAM1 phosphorylate PBL34/35/36.
Further biochemical assays revealed that PBL34/35/36 interacted with CLV1, BAM1/3, and CIKs, and were phosphorylated by CLV1 and BAM1.
BAM1: CLV1-related CLE receptor kinase
bam1_receptor_kinase
Participant: Gene Product: BAM1
Gene Product:
BAM1UniProtKB:O49545

Function

transmembrane receptor protein serine/threonine kinase activityGO:0004675

Processes

regulation of meristem structural organizationGO:0009934

Locations

plasma membraneGO:0005886

Redundant CLV3 receptor that buffers loss of CLV1. It has broader CLE specificity than CLV1, and in the meristem flanks it may also act as a ligand sink.

PMID:25754504
BAM1 binds CLV3 directly, and clv1 bam1 has an enlarged meristem with expanded WUS.
These results indicate that CLV1 and BAM1 are direct receptors that are sufficient to affect the regulatory network controlling stem cell number in the SAM.
PMID:18780746
The weak phenotype of clv1 nulls depends on BAM activity.
We show that the weak nature of the phenotype of clv1 null alleles is dependent on BAM activity
CLV2/CRN co-receptor complexProtein Complexclv2_crn_coreceptor_complex

A heteromer of the kinase-less LRR receptor-like protein CLV2 and the transmembrane pseudokinase CRN. The two subunits assemble through their transmembrane domains, and each is needed for the other to leave the ER. Radioligand assays reported CLE binding by CLV2 (Kd about 32 nM), but photoaffinity labelling did not detect it. The complex is therefore modelled as a co-receptor whose signalling depends on the CRN pseudokinase domain and on CIK kinases.

Annotons

CLV2: LRR receptor-like co-receptor
clv2_coreceptor
Participant: Gene Product: CLV2
Gene Product:
CLV2UniProtKB:O80809

Function

coreceptor activityGO:0015026

Processes

regulation of meristem growthGO:0010075

Locations

plasma membraneGO:0005886

Ectodomain-bearing subunit of the CLV2/CRN complex.

PMID:25754504
CLV2/CRN shows no direct CLV3 binding by photoaffinity labelling and may act as a co-receptor.
In contrast, the CLV2/CRN complex and RPK2 are not involved in direct ligand interactions but may act as co-receptors.
PMID:20626648
Radioligand binding gives a CLV2 Kd similar to that of CLV1 (contested).
Binding was saturable for all receptors with a very similar Kd for each receptor: 30 nM for CLV1, 32 nM for CLV2, 26 nM for BAM1, and 36 nM for BAM2
CRN: pseudokinase scaffold of the CLV2/CRN complex
crn_pseudokinase_adaptor
Participant: Gene Product: CRN
Gene Product:
CRNUniProtKB:Q9LYU7

Function

signaling receptor complex adaptor activityGO:0030159 CRN has no catalytic activity (NOT GO:0004672). Its kinase-like domain is needed for shoot signalling as a scaffold.

Processes

regulation of meristem growthGO:0010075

Locations

plasma membraneGO:0005886

Transmembrane pseudokinase that brings CLV2 to the plasma membrane and supplies the intracellular module of the complex.

PMID:19933383
CLV2 and CRN require each other for ER export and plasma-membrane localization.
We found that CLV2 and CRN require each other for export from the endoplasmic reticulum and localization to the plasma membrane (PM).
PMID:21398569
CRN lacks kinase activity, and a kinase-dead allele complements.
indicating that CRN does not require kinase activity for wild-type function
Part 4: KNOX meristem-maintenance context (optional)
STM-dependent meristem competence (context)Regulatory Stepstm_knox_context

STM keeps meristem cells undifferentiated throughout the dome. It is needed for a meristem to exist, but it is not part of the CLV3-WUS feedback circuit itself. It is included as context because stm alleles interact genetically with clv mutations.

Annotons

STM: KNOX homeodomain transcription factor
stm_tf
Participant: Gene Product: STM
Gene Product:
STMUniProtKB:Q38874

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Processes

stem cell population maintenanceGO:0019827

Locations

nucleusGO:0005634

Meristem-wide factor that prevents differentiation. It provides context for, and is not a component of, the CLV-WUS loop.

PMID:9729492
stm and clv2 alleles suppress each other.
The stm-1 mutation dominantly suppresses clv2, and clv2 mutations suppress the strong stm-1 allele, but not the weak stm-2 allele.