Our long-term goal is to define the pathogenesis of DiGeorge/velocardiofacial syndrome (DGS/VCFS) developmentally and genetically using mouse models. Heterozygous deletions at 22ql 1.2 are the molecular basis of DGS affecting many tissues whose normal development depends on neural crest cells. The genetic and developmental etiology of this syndrome is complex. The recent discovery that haploinsufficiency of Tbxl (the mouse homologue of a T-box gene mapped at 22q11.21) causes abnormal development of aortic arch arteries suggests a critical role for TBX1 in DiGeorge syndrome. Although approximately 90% of the patients have a common 3 Mb heterozygous deletion at 22ql 1.2, a significant number of syndromic patients have smaller deletions that do not overlap within the 3 Mb region. It is therefore difficult to explain this syndrome simply by a mutation of a single gene. Our recent study suggests that deletion of another 22q11.21 gene, CRKL (CRK-Like), mapped within the 3 Mb deletion region may also contribute to this syndrome. Homozygous deletion of CrkL (gene symbol Crkl) recapitulates a wide range of neural crest defects that closely mimic DGS. Furthermore, we have recently noted that haploinsufficiency of Crkl in a C57BL/6 congenic background. To provide insight into the etiology of DGS as well as the mechanisms of congenital heart defects, we propose the following specific aims: 1. To determine the developmental mechanism of the cardiovascular defects in Crkl- embryos. 2. To determine the genetic pathways in which Crkl plays a role. To address these aims, we propose the following subaims:
Sub aim 1. 1) To test the hypothesis that CrkL is required for proper neural crest contribution to the cardiovascular system;
Sub aim 1. 2) To test the hypothesis that CrkL is essential for growth or survival of cardiac neural crest derivatives;
Sub aim 2. 1) To determine the genetic hierarchy for which Crkl is essential;
Sub aim 2. 2) To test the hypothesis that CrkL is involved in signaling pathways mediated by Src family kinases;
Sub aim 2. 3) To determine the genetic interactions of Crkl with Tbxl for proper development of neural crest derivatives. ? ? ?
| Seo, Ji-Heui; Wood, Lisa J; Agarwal, Anupriya et al. (2010) A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors. Cancer Res 70:7325-35 |
| Seo, Ji-Heui; Suenaga, Atsushi; Hatakeyama, Mariko et al. (2009) Structural and functional basis of a role for CRKL in a fibroblast growth factor 8-induced feed-forward loop. Mol Cell Biol 29:3076-87 |
| Moon, Anne M; Guris, Deborah L; Seo, Ji-heui et al. (2006) Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes. Dev Cell 10:71-80 |
| Guris, Deborah L; Duester, Gregg; Papaioannou, Virginia E et al. (2006) Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev Cell 10:81-92 |
