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PMID:21262862

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Citation

Brouns, MR, De Castro, SC, Terwindt-Rouwenhorst, EA, Massa, V, Hekking, JW, Hirst, CS, Savery, D, Munts, C, Partridge, D, Lamers, W, Köhler, E, van Straaten, HW, Copp, AJ and Greene, ND (2011) Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse. Hum. Mol. Genet. 20:1536-46

Abstract

Cranial neural tube defects (NTDs) occur in mice carrying mutant alleles of many different genes, whereas isolated spinal NTDs (spina bifida) occur in fewer models, despite being common human birth defects. Spina bifida occurs at high frequency in the Axial defects (Axd) mouse mutant but the causative gene is not known. In the current study, the Axd mutation was mapped by linkage analysis. Within the critical genomic region, sequencing did not reveal a coding mutation whereas expression analysis demonstrated significant up-regulation of grainyhead-like 2 (Grhl2) in Axd mutant embryos. Expression of other candidate genes did not differ between genotypes. In order to test the hypothesis that over-expression of Grhl2 causes Axd NTDs, we performed a genetic cross to reduce Grhl2 function in Axd heterozygotes. Grhl2 loss of function mutant mice were generated and displayed both cranial and spinal NTDs. Compound heterozygotes carrying both loss (Grhl2 null) and putative gain of function (Axd) alleles exhibited normalization of spinal neural tube closure compared with Axd/+ littermates, which exhibit delayed closure. Grhl2 is expressed in the surface ectoderm and hindgut endoderm in the spinal region, overlapping with grainyhead-like 3 (Grhl3). Axd mutants display delayed eyelid closure, as reported in Grhl3 null embryos. Moreover, Axd mutant embryos exhibited increased ventral curvature of the spinal region and reduced proliferation in the hindgut, reminiscent of curly tail embryos, which carry a hypomorphic allele of Grhl3. Overall, our data suggest that defects in Axd mutant embryos result from over-expression of Grhl2.

Links

PubMed PMC3063985 Online version:10.1093/hmg/ddr031

Keywords

Animals; Cell Proliferation; Chromosome Mapping; Chromosomes, Mammalian/genetics; Female; Gene Silencing; Genetic Linkage; Humans; Hybridization, Genetic; Lower Gastrointestinal Tract/abnormalities; Lower Gastrointestinal Tract/cytology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Spinal Dysraphism/embryology; Spinal Dysraphism/genetics; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GRHL3

acts_upstream_of_or_within

GO:0061029: eyelid development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856837

P

Seeded From UniProt

complete

MOUSE:GRHL2

acts_upstream_of_or_within

GO:0001843: neural tube closure

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4331210

P

Seeded From UniProt

complete

MOUSE:GRHL2

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4331210

P

Seeded From UniProt

complete


See also

References

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