DiGeorge syndrome (DGS) is an archetypal cranial/cardiac neurocristopathy and includes aortic arch and outflow tract defects, and aplasia or hypoplasia of the thymus and parathyroids. DGS is caused by a 2-3 MB heterozygous deletion of chr. 22q11.2 (del22q11). We have generated a mouse model of del22q11 that presents with the characteristic DGS congenital heart disease. The mutant carries a targeted chromosomal deletion (Df1) which spans approximately 1Mb of DNA and eliminates most of the murine homologs homologs of the genes deleted in DGS. Molecular marker analyses in Df1/+ embryos suggests that neural crest cell migration is normal but their post-migratory differentiation is impaired. Therefore, we put forward the following hypothesis. Df1 reduces the differentiation capacity of neural crest-derived mesenchymal cells in the pharyngeal arches by impairing their ability to receive or respond to tissue interaction-mediated signals. The differentiation impairment hypothesis is consistent with preliminary data showing rescue of the Df1/+ phenotype by a transgenic DNA fragment containing a gene that is deleted in Df1 and DGS, and predicted to be important for mesodermal differentiation. While we speculate that this would be a general mechanism by which the DGS gene haploinsufficiency may cause the neurocristopathy associated with DGS, this proposal will focus on the genetic mechanisms by which Df1/+ mesenchymal cells fail to support the growth of the 4th pharyngeal arch arteries. To this end, we will first determine whether DF1/+ mesenchymal cells fail to support the growth of the 4th pharyngeal arch arteries. To this end, we will first determine whether Df1/+ mesenchymal cells are able to reach the endothelial tube and contribute to the building of the vessel wall. Next, we will address whether gene haploinsufficiency restricted to mesenchymal cells is sufficient to generate the characteristic phenotype (as predicted by our hypothesis), or alternatively, haploinsufficiency in endothelial cells is also necessary. Last, we propose to identify down stream targets of the haplosufficient gene, that we hypothesize will include members of the TGF-beta family of genes. The proposed experiments should provide insight into and initiate the dissection of a genetic pathway required for normal development of the aortic arch, involved in the pathogenesis of DiGeorge syndrome and possibly other disorders. Affecting the outflow tract of the heart.
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