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NK2 model of congenital heart disease

ABSTRACT: Lack of the conserved NK2-domain of the cardiac transcription factor Nkx2.5 causes multiple heart defects . The NK2 family of homeobox genes constitutes a family of transcription factors that play an important role in different developmental processes. Members of this group are characterized by two highly conserved protein domains: the homeodomain, conferring DNA binding activity, and the NK2-specific domain (NK2-SD) of yet unknown function. One of the best characterized members of this group is the early cardiogenic marker Nkx2.5. Loss of function of Nkx2.5 leads to embryonic lethality around E10.5 due to an arrest of heart development at the looping stage. We have further dissected the function of Nkx2.5 in vivo by creating a knockout mouse line harboring an in frame deletion of the NK2-SD by Cre/loxP mediated excision. Homozygous mutant mice die at E14.5 due to severe cardiac malformations, e.g. common AV canal, DORV, and VSD. Lack of the NK2-SD leads to downregulation of the ventricular markers MLC-2v and Irx4 specifically in the right ventricle, and is accompanied with reduced right ventricular function. This function of Nkx2.5 seems to be independent of its ability to bind target DNA, since lack of the NK2-SD does not alter the DNA binding activity of Csx/Nkx2.5 in vitro. Heterozygous mutant mice show a spectrum of cardiac defects related to cardiac septation and valve morphogenesis, but lack conduction system defects as reported for heterozygous Nkx2.5 mice. The phenotype observed in NK2-SD mutant mice shows that Nkx2.5 is not only crucial during early steps of cardiogenesis but also plays an important role at later developmental stages. Embryos were isolated at embryonic day 12.5. The entire embryo heart was taken and isolated in ice-cold PBS and immediately frozen on dry-ice. Total RNA was extracted from pooled samples of wildtype, heterozygous and mutant embryos. Keywords = congenital heart disease, Csx, Nkx2.5 Keywords: other

ORGANISM(S): Mus musculus

PROVIDER: GSE528 | GEO | 2003/07/13

SECONDARY ACCESSION(S): PRJNA85533

REPOSITORIES: GEO

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Project description:Rationale: 22q11 deletion syndrome arises from recombination between low copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack extra-cardiac features of the syndrome suggesting that a second haploinsufficient gene maps to this interval. Objective: The transcription factor HIC2 is lost in most distal deletions as well as a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease. Methods and Results: We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5 while the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. Magnetic resonance imaging demonstrated a ventricular septal defect with overriding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages but not in the Wnt1+ neural crest or Mef2c+ second heart field lineages. Microarray analysis revealed increased expression of BMP10. Conclusions: Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggests HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome. The aim of this microarray experiment was to compare gene expression changes in the E13.5 mouse heart in a conditional knockout of Hic2 (Mesp1Cre/+; Hic2FL/FL) against control. All samples represent pools of isolated hearts from E13.5 mouse embryos. 3 replicates of each genotype were assayed. The genotypes are: 'WT' (Hic2FL/FL) 'KO' (Mesp1Cre/+; Hic2 FL/FL)

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NK2 model of congenital heart disease

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