Neural crest gene regulatory network module

The vertebrate neural crest gene regulatory network: the transcriptional program by which signals at the edge of the neural plate are converted, through a neural plate border layer and a crest specifier layer, into migratory multipotent crest cells, of which the cranial population forms skeletogenic ectomesenchyme. A parallel competence layer, shared with pluripotent blastula cells, keeps progenitors undifferentiated. Border specifiers (Gbx2, Msx1, AP-2alpha, Pax3, Zic1) are largely ancestral chordate genes already expressed at the amphioxus neural plate border; most crest specifiers were recruited at the base of vertebrates, mainly by changes in where they are expressed, and some cranial circuit components (Ets1) were added later in jawed vertebrates. Inducing signals (Wnt, BMP, FGF) are covered by the wnt_signaling, bmp_signaling and FGF modules and are treated here as upstream context.

MODULE:neural_crest_gene_regulatory_networkDRAFTDevelopmental Processmodules/neural_crest_gene_regulatory_network.yaml

neural crest cell differentiationGO:0014033

PMID:25564621

Establishing neural crest identity: a gene regulatory recipe.

Review of the layered neural crest gene regulatory network (border, specifier, effector layers).

PMID:18562679

Insights from the amphioxus genome on the origin of vertebrate neural crest.

Amphioxus has border patterning genes at the neural plate border but lacks most crest specifier expression there.

neural plate border patterning genes, and melanocyte differentiation genes appear conserved

file:modules/neural_crest_gene_regulatory_network-deep-research-falcon.md

Module deep research supports treating inducing signals as upstream inputs rather than network members.

WNT, BMP and FGF signaling are upstream inputs

PMID:31645763

Evolution of the new head by gradual acquisition of neural crest regulatory circuits.

The cranial crest circuit was assembled gradually in gnathostomes; the ancestral crest was trunk-like.

Concrete members are the gene products reviewed in projects/NEURAL_CREST_ORIGINS.md: Xenopus laevis proteins where reviewed Swiss-Prot entries exist, human proteins otherwise. Process terms follow the replacement rule of projects/NEURAL_CREST_FORMATION_OBSOLETION.md: border genes at the proposed 'neural plate border formation' term (plus GO:0014034 where they directly induce crest fate), crest specifiers at GO:0014036, and competence factors at the proposed 'neural crest progenitor maintenance' term. Genes with roles in more than one layer (AP-2alpha, Snai2, Twist1, Sox9) have one annoton per role, which is how roles that are non-core at gene level (e.g. Twist1 in ectomesenchyme) become explicit parts here. Sox10-driven melanocyte and glial differentiation are downstream derivative programs and are out of scope. Both proposed terms (neural plate border formation; neural crest progenitor maintenance, proposed is_a GO:0019827) have their canonical name, definition and justification in the proposed_new_terms entries of the member gene reviews and in projects/NEURAL_CREST_FORMATION_OBSOLETION.md; they are ontology gaps, not knowledge gaps, so they are not repeated here. Not yet modelled (curation plan in projects/NEURAL_CREST_ORIGINS.md): Hairy2 acting through an FGFR4-STAT3 complex, OCT4-SOX2 redeployed to TFAP2A-bound crest enhancers (chick/human; in frog any crest Oct partner is more likely SoxE, since Sox3 is absent from crest by neurula), and the Twist1 chromatin partners CHD7/CHD8/WHSC1.

11Nodes

5Parts

2Variant Sets

5Variants

25Annotons

24Connections

Derived QC

Recommended-field compliance

78.3% recommended fields populated

knowledge_gaps[0].provenance[0] · reference_section_type (0/1)
knowledge_gaps[0].provenance[1] · reference_section_type (0/1)
knowledge_gaps[1].provenance[0] · reference_section_type (0/1)
knowledge_gaps[1].provenance[1] · reference_section_type (0/1)
knowledge_gaps[2].provenance[0] · reference_section_type (0/1)

Module deep research

✓ present

neural_crest_gene_regulatory_network-deep-research-falcon.md (falcon)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

neural_plate_border_specification → neural_crest_fate_specification [NOT_CHECKED]
neural_crest_fate_specification → neural_crest_emigration [NOT_CHECKED]
neural_crest_emigration → cranial_ectomesenchyme [NOT_CHECKED]

Function consistency and core coverage

25 gene-function check(s) reflected in core functions · 0 conflict(s) · 0 evidence or coverage gap(s) (25 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.

Annoton	Participant	Function	Assessment
gbx2_border	gbx2 UniProtKB:Q91907 Gene	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
msx1_border	MSX1 UniProtKB:P28360 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).
tfap2a_border	TFAP2A UniProtKB:P05549 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tfap2c_border	TFAP2C UniProtKB:Q92754 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
zic1_border	zic1 UniProtKB:O73689 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pax3_border	pax3-a UniProtKB:Q645N4 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pax7_border	PAX7 UniProtKB:P23759 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
myc_competence	myc-a UniProtKB:P06171 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).
id3_competence	id3-a UniProtKB:Q91399 Gene	transcription regulator inhibitor activity GO:0140416	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pou5f3_competence	pou5f1.1 UniProtKB:Q7T103 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).
hes4_competence	hes4-a UniProtKB:Q90Z12 Gene	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
foxd3_spec	foxd3-a UniProtKB:Q9DEN4 Gene	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
snai1_spec	snai1 UniProtKB:P19382 Gene	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
snai2_spec	snai2 UniProtKB:Q91924 Gene	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tfap2b_spec	TFAP2B UniProtKB:Q92481 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tfap2a_spec	TFAP2A UniProtKB:P05549 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
twist1_snai2_inhibition	twist1 UniProtKB:P13903 Gene	transcription regulator inhibitor activity GO:0140416	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sox8_spec	sox8 UniProtKB:Q6VVD7 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).
sox9_spec	sox9-a UniProtKB:B7ZR65 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sox10_spec	sox10 UniProtKB:Q8AXX8 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).
ets1_emigration	ets1-a UniProtKB:P18755 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
snai2_migration	snai2 UniProtKB:Q91924 Gene	DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
twist1_ectomesenchyme	twist1 UniProtKB:P13903 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).
sox9_chondrogenesis	sox9-a UniProtKB:B7ZR65 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tfap2a_craniofacial	TFAP2A UniProtKB:P05549 Gene	DNA-binding transcription activator activity, RNA polymerase II-specific GO:0001228	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.

tfap2b_spec ⊣ tfap2c_border [closed]
tfap2b_spec is regulated by tfap2c_border, pax3_border, zic1_border: feedback loop closed
twist1_snai2_inhibition ⊣ snai2_spec [input]
twist1_snai2_inhibition is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (20/20 grounded genes reviewed)

16 complete review(s) · 20 with deep research · 0 missing review · 0 reviewed but lacking deep research

Gene	Review	Complete	Deep research
ets1-a P18755	✓	✓	✓
foxd3-a Q9DEN4	✓	✓	✓
gbx2 Q91907	✓	✓	✓
hes4-a Q90Z12	✓	29/30	✓
id3-a Q91399	✓	✓	✓
MSX1 P28360	✓	63/65	✓
myc-a P06171	✓	✓	✓
pax3-a Q645N4	✓	✓	✓
PAX7 P23759	✓	25/26	✓
pou5f1.1 Q7T103	✓	✓	✓
snai1 P19382	✓	✓	✓
snai2 Q91924	✓	✓	✓
sox10 Q8AXX8	✓	✓	✓
sox8 Q6VVD7	✓	✓	✓
sox9-a B7ZR65	✓	✓	✓
TFAP2A P05549	✓	✓	✓
TFAP2B Q92481	✓	✓	✓
TFAP2C Q92754	✓	62/63	✓
twist1 P13903	✓	✓	✓
zic1 O73689	✓	✓	✓

Tree

Neural crest gene regulatory networkDevelopmental Processneural_crest_gene_regulatory_network

Parts
1. 1. define the neural plate border competence territory
2. Neural plate border specificationDevelopmental Processneural_plate_border_specification
  
  Annotons
  - Gbx2 border specifier Gene Product: gbx2
  - Msx1 border specifier Gene Product: MSX1
  - AP-2alpha border initiator Gene Product: TFAP2A
  - AP-2gamma (TFAP2A–TFAP2C) border inducer Gene Product: TFAP2C
  - Zic1 border specifier Gene Product: zic1
  Variants
  1. Pax3/7 border specifier (paralog deployment differs by lineage) by Pax3/7 paralog / vertebrate lineage (One Or More)
    
    Pax3 (lead paralog in frog)Developmental Processpax3_variant
    
    Annotons
    
    Pax3 border specifier Gene Product: pax3-a
    
    Pax7 (lead paralog in chick)Developmental Processpax7_variant
    
    Annotons
    
    Pax7 border specifier Gene Product: PAX7
3. 1. keep border and crest progenitors undifferentiated and proliferative
4. Maintenance of border/crest progenitor competenceDevelopmental Processprogenitor_competence_maintenance
  
  Annotons
  - c-Myc competence factor Gene Product: myc-a
  - Id3 bHLH inhibitor Gene Product: id3-a
  - Oct25 (Pou5f3) competence factor Gene Product: pou5f1.1
  - Hairy2 border repressor Gene Product: hes4-a
5. 2. specify neural crest identity
6. Neural crest fate specificationDevelopmental Processneural_crest_fate_specification
  
  Annotons
  - FoxD3 crest specifier Gene Product: foxd3-a
  - Snail1 early crest specifier Gene Product: snai1
  - Snai2 crest specifier Gene Product: snai2
  - AP-2beta (TFAP2A–TFAP2B) crest specifier Gene Product: TFAP2B
  - AP-2alpha crest specifier Gene Product: TFAP2A
  - Twist1 restraint of Snai2 Gene Product: twist1
  Variants
  1. SoxE crest specifier (paralog deployment differs by lineage) by SoxE paralog / vertebrate lineage (One Or More)
    
    Sox8 (first-wave SoxE in frog)Developmental Processsox8_variant
    
    Annotons
    
    Sox8 crest specifier Gene Product: sox8
    
    Sox9Developmental Processsox9_variant
    
    Annotons
    
    Sox9 crest specifier Gene Product: sox9-a
    
    Sox10Developmental Processsox10_variant
    
    Annotons
    
    Sox10 crest specifier Gene Product: sox10
7. 3. delaminate and migrate
8. Neural crest delamination and migrationDevelopmental Processneural_crest_emigration
  
  Annotons
  - Ets1 delamination effector Gene Product: ets1-a
  - Snai2 migration effector Gene Product: snai2
9. 4. form cranial skeletogenic ectomesenchyme
10. Cranial crest ectomesenchyme and skeletogenesisDevelopmental Processcranial_ectomesenchyme
  
  Annotons
  - Twist1 ectomesenchyme driver Gene Product: twist1
  - Sox9 crest chondrogenesis Gene Product: sox9-a
  - AP-2alpha craniofacial morphogenesis Gene Product: TFAP2A

Details

Context

VertebrataNCBITaxon:7742

nucleusGO:0005634

Neural crest gene regulatory networkDevelopmental Processneural_crest_gene_regulatory_network

neural crest cell differentiationGO:0014033

Context

VertebrataNCBITaxon:7742

nucleusGO:0005634

Connections

neural_plate_border_specification -> neural_crest_fate_specification Precedes

Border specifiers are expressed first and are required for crest specifier expression.

progenitor_competence_maintenance -> neural_crest_fate_specification Provides Input For

Competence factors keep border progenitors undifferentiated so that specifier inputs can act.

neural_crest_fate_specification -> neural_crest_emigration Precedes

Specified crest cells delaminate and migrate.

neural_crest_emigration -> cranial_ectomesenchyme Precedes

Migrating cranial crest populates the pharyngeal arches and forms skeletogenic ectomesenchyme.

gbx2_border -> pax3_border Positively Regulates

Gbx2 acts upstream of Pax3, placed by epistasis; direct binding to the pax3 locus is not demonstrated.

file:modules/neural_crest_gene_regulatory_network-deep-research-falcon.md

Module deep research (falcon) assessment of this edge.

Gbx2 is positioned upstream of *msx1* and *pax3* by epistasis

gbx2_border -> msx1_border Positively Regulates

Gbx2 acts upstream of Msx1, placed by epistasis; direct binding to the msx1 locus is not demonstrated.

file:modules/neural_crest_gene_regulatory_network-deep-research-falcon.md

Module deep research (falcon) assessment of this edge.

Gbx2 is positioned upstream of *msx1* and *pax3* by epistasis

tfap2a_border -> pax3_border Positively Regulates

AP-2alpha activates pax3 directly: translation-independent induction, promoter-reporter, site mutation and EMSA/supershift (frog).

file:modules/neural_crest_gene_regulatory_network-deep-research-falcon.md

Module deep research (falcon) assessment of this edge.

A stronger direct edge is AP-2α → *pax3*

msx1_border -> pax3_border Positively Regulates

Msx1 induces Pax3 cell-autonomously.

msx1_border -> zic1_border Positively Regulates

Msx1 induces ZicR1/Zic cell-autonomously.

pax3_border -> snai2_spec Positively Regulates

Pax3 binds and activates snail2 directly.

pax3_border -> foxd3_spec Positively Regulates

Pax3/Zic1 activate foxd3 without new protein synthesis (immediate-response target); enhancer occupancy in frog not shown.

zic1_border -> foxd3_spec Positively Regulates

Pax3/Zic1 activate foxd3 without new protein synthesis (immediate-response target); enhancer occupancy in frog not shown.

zic1_border -> snai1_spec Positively Regulates

Zic1 binds a snail1 element (EMSA) and activates snail1 without new protein synthesis.

snai1_spec -> snai2_spec Positively Regulates

Snail1 acts upstream of Slug/Snai2 in crest specification.

tfap2c_border -> tfap2b_spec Positively Regulates

TFAP2A/C occupies the TFAP2B locus and is required for its activation at the onset of specification (chick).

tfap2b_spec -> tfap2c_border Negatively Regulates

TFAP2B represses TFAP2C cell-autonomously, stabilising the switch from the A/C to the A/B heterodimer (chick).

pax3_border -> tfap2b_spec Positively Regulates

Pax3/Zic1 activate tfap2b without new protein synthesis (frog immediate-response target).

zic1_border -> tfap2b_spec Positively Regulates

Pax3/Zic1 activate tfap2b without new protein synthesis (frog immediate-response target).

pax7_border -> foxd3_spec Positively Regulates

Pax7 binds the FoxD3 NC1 enhancer in vivo (ChIP) with Msx1 and Ets1; its knockdown abolishes NC1/NC2 activity (chick).

pou5f3_competence -> pax3_border Positively Regulates

Pou5f3 gain of function expands pax3 (and zic1, snai2) expression.

pax3_border -> sox8_spec Positively Regulates

Pax3/Zic1 activate sox8 with snail1 and myc.

pax3_border -> twist1_ectomesenchyme Positively Regulates

Pax3 activates twist1 directly.

twist1_snai2_inhibition -> snai2_spec Negatively Regulates

Twist binds Snai2 and reduces its chromatin occupancy. Stage-specific: Twist later promotes mesenchymal outputs, so this is not a permanent inhibitory edge.

file:modules/neural_crest_gene_regulatory_network-deep-research-falcon.md

Module deep research (falcon) assessment of this edge.

a permanently activating or permanently inhibiting “TWIST → SNAI2” arrow misstates the mechanism

hes4_competence -> id3_competence Provides Input For

Hairy2 and Id3 act together (with Stat3) to keep progenitors undifferentiated.

Part 1: define the neural plate border competence territory

Neural plate border specificationDevelopmental Processneural_plate_border_specification

Wnt, intermediate BMP and FGF signals at the edge of the neural plate are read out by a set of transcription factors that define the neural plate border, a competence territory that gives rise to neural crest, preplacodal ectoderm, dorsal neural tube and epidermis. Border specifiers act upstream of, and are required for, crest specifier expression, but individually do not impose crest fate; Pax3 and Zic1 together are necessary and sufficient to do so.

neural plate border formation (proposed new term)

Annotons

Gbx2 border specifier

gbx2_border

Participant: Gene Product: gbx2

Gene Product:

gbx2UniProtKB:Q91907 Xenopus laevis gbx2; reviewed in genes/XENLA/gbx2/.

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Processes

neural plate border formation (proposed new term; replaces GO:0014029, proposed for obsoletion)

Locations

nucleusGO:0005634

Wnt-responsive repressor acting upstream of the border factors Pax3 and Msx1; required for crest and limits the preplacodal domain.

PMID:19736322

The posteriorizing gene Gbx2 is a direct target of Wnt signalling and the earliest factor in neural crest induction.

Gbx2 is required for neural crest and acts upstream of the border factors Pax3 and Msx1.

Loss-of-function experiments using antisense morpholinos against Gbx2 inhibit NC and expand the preplacodal domain, whereas Gbx2 overexpression leads to transformation of the preplacodal domain into NC cells.

PMID:19736322

The posteriorizing gene Gbx2 is a direct target of Wnt signalling and the earliest factor in neural crest induction.

Gbx2 is required for neural crest and acts upstream of the border factors Pax3 and Msx1.

In addition, we demonstrate that Gbx2 is upstream of the neural fold specifiers Pax3 and Msx1.

Msx1 border specifier

msx1_border

Participant: Gene Product: MSX1

Gene Product:

MSX1UniProtKB:P28360 Homo sapiens MSX1; reviewed in genes/human/MSX1/.

Function

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

Processes

neural plate border formation (proposed new term; replaces GO:0014029, proposed for obsoletion)

Locations

nucleusGO:0005634

BMP-responsive homeodomain factor at the neural fold; induces Pax3 and Zic cell-autonomously.

PMID:14627721

Regulation of Msx genes by a Bmp gradient is essential for neural crest specification.

Intermediate BMP specifies Msx expression at the border, and Msx1 induces Pax3 and Zic.

Our results indicate that an intermediate level of Bmp activity specifies the expression of Msx genes in the neural fold region.

PMID:15691759

Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction.

Intermediate BMP specifies Msx expression at the border, and Msx1 induces Pax3 and Zic.

Msx1 induces Pax3 and ZicR1 cell autonomously, in turn, Pax3 combined with ZicR1 activates Slug in a WNT-dependent manner.

AP-2alpha border initiator

tfap2a_border

Participant: Gene Product: TFAP2A

Gene Product:

TFAP2AUniProtKB:P05549 Homo sapiens TFAP2A; reviewed in genes/human/TFAP2A/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural plate border formation (proposed new term; replaces GO:0014029, proposed for obsoletion)

Locations

nucleusGO:0005634

Earliest known border specifier; mediates Wnt input to initiate the border and activate pax3.

PMID:21169220

Reiterative AP2a activity controls sequential steps in the neural crest gene regulatory network.

AP-2alpha initiates neural plate border patterning and activates pax3.

As the earliest known NB specifier, AP2a mediates Wnt signals to initiate the NB and activate pax3; as a NC specifier, AP2a regulates further NC development independent of and downstream of NB patterning.

PMID:21169220

Reiterative AP2a activity controls sequential steps in the neural crest gene regulatory network.

AP-2alpha initiates neural plate border patterning and activates pax3.

AP2a initiates NB patterning and is sufficient to elicit a NB-like pattern in neuralized ectoderm.

AP-2gamma (TFAP2A–TFAP2C) border inducer

tfap2c_border

Participant: Gene Product: TFAP2C

Gene Product:

TFAP2CUniProtKB:Q92754 Homo sapiens TFAP2C; reviewed in genes/human/TFAP2C/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural plate border formation (proposed new term; replaces GO:0014029, proposed for obsoletion)

Locations

nucleusGO:0005634

Partners TFAP2A as a heterodimer during border induction; lost from crest at specification, when TFAP2B replaces it.

PMID:31848212

Heterodimerization of TFAP2 pioneer factors drives epigenomic remodeling during neural crest specification.

TFAP2A/C heterodimers mediate neural plate border induction.

TFAP2C knockdown during induction resulted in a down-regulation of the neural plate border markers MSX1, PAX7, ZIC1, and GBX2 but had no significant effects on the expression of specification genes FOXD3, ETS1, SOX9, and SOX10

PMID:31848212

Heterodimerization of TFAP2 pioneer factors drives epigenomic remodeling during neural crest specification.

TFAP2A/C heterodimers mediate neural plate border induction.

TFAP2A/C heterodimers mediate neural plate border induction, whereas TFAP2A/B heterodimers promote neural crest specification

Zic1 border specifier

zic1_border

Participant: Gene Product: zic1

Gene Product:

zic1UniProtKB:O73689 Xenopus laevis zic1; reviewed in genes/XENLA/zic1/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural plate border formation (proposed new term; replaces GO:0014029, proposed for obsoletion) neural crest cell fate commitmentGO:0014034

Locations

nucleusGO:0005634

Zinc-finger activator at the border; with Pax3 commits cells to crest, alone promotes preplacodal or neural fates.

PMID:15843410

Neural crest determination by co-activation of Pax3 and Zic1 genes in Xenopus ectoderm.

Pax3 and Zic1 are early border factors, necessary and sufficient to promote crest fate.

Pax3 and Zic1 are expressed in an overlapping manner in the presumptive neural crest area of the Xenopus gastrula, even prior to the onset of the expression of the early bona fide neural crest marker genes Foxd3 and Slug.

PMID:24360908

Identification of Pax3 and Zic1 targets in the developing neural crest.

Pax3 and Zic1 are early border factors, necessary and sufficient to promote crest fate.

Transcription factors pax3 and zic1 are among the earliest genes activated in NC progenitors, and they are both necessary and sufficient to promote NC fate.

Variant set: Pax3/7 border specifier (paralog deployment differs by lineage) by Pax3/7 paralog / vertebrate lineage (One Or More)

Frog leads with Pax3, chick with Pax7, and mouse uses both redundantly; amphioxus has a single Pax3/7 at the border.

Pax3 (lead paralog in frog)Developmental Processpax3_variant

Annotons

Pax3 border specifier

pax3_border

Participant: Gene Product: pax3-a

Gene Product:

pax3-aUniProtKB:Q645N4 Xenopus laevis pax3-a; reviewed in genes/XENLA/pax3-a/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural plate border formation (proposed new term; replaces GO:0014029, proposed for obsoletion) neural crest cell fate commitmentGO:0014034

Locations

nucleusGO:0005634

Paired-box activator at the border; with Zic1 directly activates crest specifier genes.

PMID:24360906

Pax3 and Zic1 trigger the early neural crest gene regulatory network by the direct activation of multiple key neural crest specifiers.

Pax3 and Zic1 directly activate the crest specifier genes.

We demonstrated that the neural border specifiers Pax3 and Zic1 are direct upstream regulators of neural crest specifiers Snail1/2, Foxd3, Twist1, and Tfap2b.

PMID:24360906

Pax3 and Zic1 trigger the early neural crest gene regulatory network by the direct activation of multiple key neural crest specifiers.

Pax3 and Zic1 directly activate the crest specifier genes.

We showed that Pax3 binds efficiently to snail2 oligonucleotide but much less to the oligonucleotide mutated in the putative binding site (Figure 4D).

Pax7 (lead paralog in chick)Developmental Processpax7_variant

Annotons

Pax7 border specifier

pax7_border

Participant: Gene Product: PAX7

Gene Product:

PAX7UniProtKB:P23759 Homo sapiens PAX7; reviewed in genes/human/PAX7/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural plate border formation (proposed new term; replaces GO:0014029, proposed for obsoletion)

Locations

nucleusGO:0005634

Paired-box border factor required for crest specifier expression in chick; binds the FoxD3 NC1 enhancer with Msx1 and Ets1.

PMID:16688176

Specification of the neural crest occurs during gastrulation and requires Pax7.

Pax7 is required for crest formation and binds the FoxD3 NC1 enhancer.

In chicken embryos, Pax7 is required for neural crest formation in vivo, because blocking its translation inhibits expression of the neural crest markers Slug, Sox9, Sox10 and HNK-1.

PMID:23284303

Dynamic and differential regulation of stem cell factor FoxD3 in the neural crest is Encrypted in the genome.

Pax7 is required for crest formation and binds the FoxD3 NC1 enhancer.

Detailed regulatory analysis shows that initial expression of FoxD3 in both cranial and trunk neural crest requires direct input from neural plate border genes, Pax7 and Msx1/2.

Part 1: keep border and crest progenitors undifferentiated and proliferative

Maintenance of border/crest progenitor competenceDevelopmental Processprogenitor_competence_maintenance

Factors shared with the pluripotent blastula keep border and premigratory crest progenitors proliferative and undifferentiated, preserving the broad potential that crest cells later deploy. Loss causes progenitor arrest or death rather than a switch to another fate, so these factors support crest formation without specifying crest identity. No GO process term captures this role; a new term, neural crest progenitor maintenance, is proposed for it.

neural crest progenitor maintenance (proposed new term)

Annotons

c-Myc competence factor

myc_competence

Participant: Gene Product: myc-a

Gene Product:

myc-aUniProtKB:P06171 Xenopus laevis myc-a; reviewed in genes/XENLA/myc-a/.

Function

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

Processes

neural crest progenitor maintenance (proposed new term; replaces GO:0014029, proposed for obsoletion)

Locations

nucleusGO:0005634

Blastula-inherited Myc/Max E-box factor at the border before slug; required for crest precursors.

PMID:12791268

The protooncogene c-myc is an essential regulator of neural crest formation in xenopus.

c-Myc is at the border before slug and is required for crest precursors.

c-myc is localized at the neural plate border prior to the expression of early neural crest markers, such as slug

PMID:12791268

The protooncogene c-myc is an essential regulator of neural crest formation in xenopus.

c-Myc is at the border before slug and is required for crest precursors.

A morpholino-mediated "knockdown" of c-Myc protein results in the absence of neural crest precursor cells and a resultant loss of neural crest derivatives

Id3 bHLH inhibitor

id3_competence

Participant: Gene Product: id3-a

Gene Product:

id3-aUniProtKB:Q91399 Xenopus laevis id3-a; reviewed in genes/XENLA/id3-a/.

Function

transcription regulator inhibitor activityGO:0140416

Processes

neural crest progenitor maintenance (proposed new term; replaces GO:0014029, proposed for obsoletion) negative regulation of cell differentiationGO:0045596

Locations

nucleusGO:0005634

Dominant-negative HLH protein that keeps crest progenitors cycling and undifferentiated.

PMID:15769946

To proliferate or to die: role of Id3 in cell cycle progression and survival of neural crest progenitors.

Id3 maintains the cycling crest progenitor pool rather than specifying crest fate.

This appears to be mediated by cell cycle inhibition followed by cell death of the neural crest progenitor pool, rather than a cell fate switch.

PMID:15769946

To proliferate or to die: role of Id3 in cell cycle progression and survival of neural crest progenitors.

Id3 maintains the cycling crest progenitor pool rather than specifying crest fate.

overexpression of Id3 increases cell proliferation and results in expansion of the neural crest domain

Oct25 (Pou5f3) competence factor

pou5f3_competence

Participant: Gene Product: pou5f1.1

Gene Product:

pou5f1.1UniProtKB:Q7T103 Xenopus laevis pou5f1.1; reviewed in genes/XENLA/pou5f1.1/.

Function

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

Processes

neural crest progenitor maintenance (proposed new term; replaces GO:0014029, proposed for obsoletion)

Locations

nucleusGO:0005634

POU-V blastula pluripotency factor retained at the neural plate border; required (with its paralog) for snai2 and foxd3, and its gain expands border and crest markers.

PMID:39060477

Shared features of blastula and neural crest stem cells evolved at the base of vertebrates.

Pou5f3 is expressed at the border and is required for crest specifier expression.

zygotic pou5f3.1 and pou5f3.2 expressed in the neural plate border and neural crest

PMID:39060477

Shared features of blastula and neural crest stem cells evolved at the base of vertebrates.

Pou5f3 is expressed at the border and is required for crest specifier expression.

pou5f3 depletion resulted in a near-total loss of snai2 and foxd3 neural crest expression

Hairy2 border repressor

hes4_competence

Participant: Gene Product: hes4-a

Gene Product:

hes4-aUniProtKB:Q90Z12 Xenopus laevis hes4-a; reviewed in genes/XENLA/hes4-a/.

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Processes

neural crest progenitor maintenance (proposed new term; replaces GO:0014029, proposed for obsoletion) negative regulation of BMP signaling pathwayGO:0030514

Locations

nucleusGO:0005634

bHLH-Orange repressor that holds border cells undifferentiated and tunes Bmp4 levels at the border.

PMID:14681193

Interplay between Notch signaling and the homeoprotein Xiro1 is required for neural crest induction in Xenopus embryos.

Hairy2 keeps border cells undifferentiated and tunes Bmp4 at the border.

ensuring that levels of Bmp4 optimal for the specification of the neural plate border are attained in this region

PMID:18721802

Hairy2-Id3 interactions play an essential role in Xenopus neural crest progenitor specification.

Hairy2 keeps border cells undifferentiated and tunes Bmp4 at the border.

Hairy2 acts downstream of FGF and BMP signals at the neural border to maintain cells in an undifferentiated state

Part 2: specify neural crest identity

Neural crest fate specificationDevelopmental Processneural_crest_fate_specification

Border inputs switch on a set of crest specifier transcription factors in the prospective crest. They act within the crest domain, cross-regulate one another, and are required for, and in combination sufficient for, crest identity.

neural crest cell fate specificationGO:0014036

Annotons

FoxD3 crest specifier

foxd3_spec

Participant: Gene Product: foxd3-a

Gene Product:

foxd3-aUniProtKB:Q9DEN4 Xenopus laevis foxd3-a; reviewed in genes/XENLA/foxd3-a/.

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Processes

neural crest cell fate commitmentGO:0014034

Locations

nucleusGO:0005634

Forkhead repressor recruiting Groucho/TLE; induces crest markers when overexpressed.

PMID:11493569

Requirement of FoxD3-class signaling for neural crest determination in Xenopus.

FoxD3 is expressed in the presumptive crest and induces crest markers.

Expression of FoxD3 in the presumptive neural crest region starts at the late gastrula stage in a manner similar to that of Slug, and overlaps with that of Zic-r1.

PMID:11493569

Requirement of FoxD3-class signaling for neural crest determination in Xenopus.

FoxD3 is expressed in the presumptive crest and induces crest markers.

When overexpressed in the embryo and in ectodermal explants, FoxD3 induces expression of neural crest markers.

Snail1 early crest specifier

snai1_spec

Participant: Gene Product: snai1

Gene Product:

snai1UniProtKB:P19382 Xenopus laevis snai1; reviewed in genes/XENLA/snai1/.

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

Earliest crest specifier, activated in the first wave with sox8 and myc and directly by Zic1; acts upstream of Snai2. Also expressed in pluripotent blastula cells.

PMID:23509273

Pax3 and Zic1 drive induction and differentiation of multipotent, migratory, and functional neural crest in Xenopus embryos.

Snail1 is an early, Zic1-responsive crest specifier activated with sox8 and myc.

Indeed, a group of early genes ( snail1 , sox8 , and myc ) was activated during early neurulation

PMID:24360906

Pax3 and Zic1 trigger the early neural crest gene regulatory network by the direct activation of multiple key neural crest specifiers.

Snail1 is an early, Zic1-responsive crest specifier activated with sox8 and myc.

Zic1 binds to snail1 putative oligonucleotide

Snai2 crest specifier

snai2_spec

Participant: Gene Product: snai2

Gene Product:

snai2UniProtKB:Q91924 Xenopus laevis snai2; reviewed in genes/XENLA/snai2/.

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

E-box repressor required to form crest precursors; acts downstream of the border factors.

PMID:10772801

Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration.

Snai2 is required to form crest precursors and acts downstream of Zic1/Pax3.

inhibition of XSlug function at early stages prevents the formation of neural crest precursors, while inhibition at later stages interferes with neural crest migration

PMID:25617436

Snail2/Slug cooperates with Polycomb repressive complex 2 (PRC2) to regulate neural crest development.

Snai2 is required to form crest precursors and acts downstream of Zic1/Pax3.

By contrast, knockdown of Snail2 did not appreciably diminish either Zic1 or Pax3 levels

AP-2beta (TFAP2A–TFAP2B) crest specifier

tfap2b_spec

Participant: Gene Product: TFAP2B

Gene Product:

TFAP2BUniProtKB:Q92481 Homo sapiens TFAP2B; reviewed in genes/human/TFAP2B/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

Comes on at the onset of specification, heterodimerises with TFAP2A and recruits it to specification enhancers; represses TFAP2C.

PMID:31848212

Heterodimerization of TFAP2 pioneer factors drives epigenomic remodeling during neural crest specification.

TFAP2B is required for crest specification but not the border, and recruits TFAP2A to specification enhancers.

TFAP2B knockdown produced no effects on the neural plate border but resulted in the disruption of the specification program

PMID:31848212

Heterodimerization of TFAP2 pioneer factors drives epigenomic remodeling during neural crest specification.

TFAP2B is required for crest specification but not the border, and recruits TFAP2A to specification enhancers.

Together, these data support the idea that TFAP2B is required for the recruitment of TFAP2A to specification loci.

AP-2alpha crest specifier

tfap2a_spec

Participant: Gene Product: TFAP2A

Gene Product:

TFAP2AUniProtKB:P05549 Homo sapiens TFAP2A; reviewed in genes/human/TFAP2A/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

Second, crest-intrinsic deployment of AP-2alpha after its border role.

PMID:21169220

Reiterative AP2a activity controls sequential steps in the neural crest gene regulatory network.

AP-2alpha acts again as a crest specifier after initiating the border.

Twist1 restraint of Snai2

twist1_snai2_inhibition

Participant: Gene Product: twist1

Gene Product:

twist1UniProtKB:P13903 Xenopus laevis twist1; reviewed in genes/XENLA/twist1/.

Function

transcription regulator inhibitor activityGO:0140416

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

Twist binds Snai2 directly and reduces its chromatin occupancy, restraining Snai2-driven crest expansion.

PMID:23443570

Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

Twist binds Snai2 directly and reduces its recruitment to chromatin.

Importantly, the effects of Twist depletion can be rescued by a form of Twist that cannot be targeted by the MO

PMID:23443570

Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

Twist binds Snai2 directly and reduces its recruitment to chromatin.

suggesting that the cells that did not express NC markers were stalled in a NPB state and/or adopted alternative fates, such as placodes

Variant set: SoxE crest specifier (paralog deployment differs by lineage) by SoxE paralog / vertebrate lineage (One Or More)

Which SoxE paralog leads crest specification varies: Sox8 in frog, Sox9 in chick and mouse, sox9a/b in zebrafish, independently duplicated SoxE1/2 in lamprey. The specifier role belongs to the SoxE group; paralog-specific crest roles should not be transferred by orthology.

Sox8 (first-wave SoxE in frog)Developmental Processsox8_variant

Annotons

Sox8 crest specifier

sox8_spec

Participant: Gene Product: sox8

Gene Product:

sox8UniProtKB:Q6VVD7 Xenopus laevis sox8; reviewed in genes/XENLA/sox8/.

Function

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

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

Earliest SoxE at the lateral neural plate edge; knockdown delays crest induction.

PMID:16943273

Functional analysis of Sox8 during neural crest development in Xenopus.

Sox8 knockdown delays crest progenitor induction.

Although morpholino-mediated knockdown of Sox8 protein did not prevent the formation of neural crest progenitors, the timing of their induction was severely affected

PMID:23509273

Pax3 and Zic1 drive induction and differentiation of multipotent, migratory, and functional neural crest in Xenopus embryos.

Sox8 knockdown delays crest progenitor induction.

a group of early genes ( snail1 , sox8 , and myc ) was activated during early neurulation (between stages 12 and 15)

Sox9Developmental Processsox9_variant

Annotons

Sox9 crest specifier

sox9_spec

Participant: Gene Product: sox9-a

Gene Product:

sox9-aUniProtKB:B7ZR65 Xenopus laevis sox9-a; reviewed in genes/XENLA/sox9-a/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

SoxE activator required for crest specification but not migration.

PMID:11807034

The transcription factor Sox9 is required for cranial neural crest development in Xenopus.

Sox9 is an activator required for crest specification, not migration.

causes a dramatic loss of neural crest progenitors and an expansion of the neural plate

PMID:15464575

Early requirement of the transcriptional activator Sox9 for neural crest specification in Xenopus.

Sox9 is an activator required for crest specification, not migration.

we show that Sox9 function is required for neural crest specification but not for its subsequent migration

Sox10Developmental Processsox10_variant

Annotons

Sox10 crest specifier

sox10_spec

Participant: Gene Product: sox10

Gene Product:

sox10UniProtKB:Q8AXX8 Xenopus laevis sox10; reviewed in genes/XENLA/sox10/.

Function

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

Processes

neural crest cell fate specificationGO:0014036

Locations

nucleusGO:0005634

SoxE factor acting in the earliest steps of crest specification; later drives pigment and glial lineages.

PMID:12885557

Sox10 is required for the early development of the prospective neural crest in Xenopus embryos.

Sox10 acts early in crest specification and expands the Slug domain.

This effect of Sox10 depletion is produced during some of the earliest steps of neural crest specification

PMID:12812785

Sox10 regulates the development of neural crest-derived melanocytes in Xenopus.

Sox10 acts early in crest specification and expands the Slug domain.

Overexpression of Sox10 causes a dramatic expansion of the Slug expression domain

Part 3: delaminate and migrate

Neural crest delamination and migrationDevelopmental Processneural_crest_emigration

Specified crest cells lose adhesion to the neural tube, delaminate and migrate along stereotyped routes. Some specifier factors are redeployed here as effectors.

neural crest cell delaminationGO:0036032 neural crest cell migrationGO:0001755

Annotons

Ets1 delamination effector

ets1_emigration

Participant: Gene Product: ets1-a

Gene Product:

ets1-aUniProtKB:P18755 Xenopus laevis ets1-a; reviewed in genes/XENLA/ets1-a/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

neural crest cell delaminationGO:0036032 neural crest cell migrationGO:0001755

Locations

nucleusGO:0005634

Ets activator required in the crest for delamination and migration; part of the cranial crest circuit in jawed vertebrates.

PMID:25691536

Dual developmental role of transcriptional regulator Ets1 in Xenopus cardiac neural crest vs. heart mesoderm.

Ets1 knockdown in the crest disrupts delamination and migration.

Using a translation-blocking antisense morpholino to knockdown Ets1 protein selectively in the NC, we observed defects in NC delamination from the neural tube, collective cell migration, as well as segregation of NC streams in the cranial and cardiac regions.

Snai2 migration effector

snai2_migration

Participant: Gene Product: snai2

Gene Product:

snai2UniProtKB:Q91924 Xenopus laevis snai2; reviewed in genes/XENLA/snai2/.

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Processes

neural crest cell migrationGO:0001755

Locations

nucleusGO:0005634

Later Snai2 activity, recruiting PRC2 to the E-cadherin promoter, is required for crest migration.

PMID:25617436

Snail2/Slug cooperates with Polycomb repressive complex 2 (PRC2) to regulate neural crest development.

Late Snai2 activity is required for crest migration.

The data thus demonstrate that Snail2 helps to recruit PRC2 to the E-cad promoter to set up repressive histone modification marks that result in inhibition of E-cad expression during neural crest EMT.

PMID:10772801

Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration.

Late Snai2 activity is required for crest migration.

inhibition of XSlug function at early stages prevents the formation of neural crest precursors, while inhibition at later stages interferes with neural crest migration

Part 4: form cranial skeletogenic ectomesenchyme

Cranial crest ectomesenchyme and skeletogenesisDevelopmental Processcranial_ectomesenchyme

Cranial crest cells adopt an ectomesenchymal, skeletogenic fate and build the cartilage and bone of the head. This is the vertebrate-specific output most associated with the 'new head'.

embryonic cranial skeleton morphogenesisGO:0048701

Annotons

Twist1 ectomesenchyme driver

twist1_ectomesenchyme

Participant: Gene Product: twist1

Gene Product:

twist1UniProtKB:P13903 Xenopus laevis twist1; reviewed in genes/XENLA/twist1/.

Function

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

Processes

embryonic cranial skeleton morphogenesisGO:0048701

Locations

nucleusGO:0005634

bHLH factor that steers cranial crest to cartilage-forming ectomesenchyme; without it, cells lose Sox9 and drift toward glial fates.

PMID:23443570

Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

Twist depletion loses Sox9 in the branchial arches and head cartilage.

At stage 28, injected embryos exhibited reduced expression of Sox9 in the branchial arches, where it marks developing chondrocytes (Fig. 1f) and by stage 43 profound defects in cartilage formation and morphogenesis were observed

PMID:23443570

Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

Twist depletion loses Sox9 in the branchial arches and head cartilage.

suggesting that in the absence of Twist, cranial NC cells that would normally give rise to cartilage might instead adopt glial fates

Sox9 crest chondrogenesis

sox9_chondrogenesis

Participant: Gene Product: sox9-a

Gene Product:

sox9-aUniProtKB:B7ZR65 Xenopus laevis sox9-a; reviewed in genes/XENLA/sox9-a/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

chondrocyte differentiationGO:0002062

Locations

nucleusGO:0005634

SoxE activator required for crest-derived cranial cartilage.

PMID:11807034

The transcription factor Sox9 is required for cranial neural crest development in Xenopus.

Sox9 knockdown removes crest-derived skeletal elements.

morpholino-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements

AP-2alpha craniofacial morphogenesis

tfap2a_craniofacial

Participant: Gene Product: TFAP2A

Gene Product:

TFAP2AUniProtKB:P05549 Homo sapiens TFAP2A; reviewed in genes/human/TFAP2A/.

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

embryonic cranial skeleton morphogenesisGO:0048701

Locations

nucleusGO:0005634

AP-2alpha in crest is required for face, skull and palate morphogenesis.

PMID:8622765

Transcription factor AP-2 essential for cranial closure and craniofacial development.

Tfap2a loss, including crest-specific loss, causes craniofacial and palate defects.

AP-2(-/-) mice died perinatally with cranio-abdominoschisis and severe dismorphogenesis of the face, skull, sensory organs and cranial ganglia.

PMID:14975722

Wnt1-Cre-mediated deletion of AP-2alpha causes multiple neural crest-related defects.

Tfap2a loss, including crest-specific loss, causes craniofacial and palate defects.

Neural crest-specific disruption of tcfap2a results in frequent perinatal lethality associated with neural tube closure defects and cleft secondary palate.