Developmental/Genetic Analysis of DiGeoge Models

描述（由申请人提供）：我们的长期目标是利用小鼠模型从发育和遗传学角度确定digegeorge / velocity cardiofacial syndrome （DGS/VCFS）的发病机制。22ql 1.2的杂合缺失是DGS的分子基础，影响许多正常发育依赖于神经嵴细胞的组织。这种综合征的遗传和发育病因是复杂的。最近发现TBX1（定位于22q11.21的T-box基因的小鼠同源物）的单倍性不足导致主动脉弓动脉异常发育，这表明TBX1在DiGeorge综合征中起关键作用。虽然大约90%的患者在22ql 1.2时有一个常见的3mb杂合缺失，但相当数量的综合征患者在3mb区域内有较小的缺失，且不重叠。因此，很难简单地用单个基因的突变来解释这种综合征。我们最近的研究表明，另一个位于3mb缺失区域的22q11.21基因CRKL （CRK-Like）的缺失也可能导致这种综合征。CrkL（基因符号CrkL）的纯合缺失概括了广泛的神经嵴缺陷，与DGS非常相似。此外，我们最近注意到C57BL/6基因背景下Crkl的单倍性不足。为了深入了解先天性心脏缺陷的病因和机制，我们提出以下具体目标：1.先天性心脏缺陷；目的：探讨Crkl-胚胎心血管缺陷的发育机制。2. 确定Crkl发挥作用的遗传途径。为了实现这些目标，我们提出以下子目标：子目标1.1)检验CrkL是神经嵴对心血管系统的适当贡献所必需的假设；1.2)验证CrkL对心脏神经嵴衍生物的生长或存活至关重要的假设；Subaim 2.1)确定Crkl对其至关重要的遗传层次；Subaim 2.2)验证CrkL参与Src家族激酶介导的信号通路的假设；Subaim 2.3)确定Crkl与Tbxl的遗传相互作用对神经嵴衍生物正常发育的影响。

DESCRIPTION (provided by applicant): 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: Subaim 1.1) To test the hypothesis that CrkL is required for proper neural crest contribution to the cardiovascular system; Subaim 1.2) To test the hypothesis that CrkL is essential for growth or survival of cardiac neural crest derivatives; Subaim 2.1) To determine the genetic hierarchy for which Crkl is essential; Subaim 2.2) To test the hypothesis that CrkL is involved in signaling pathways mediated by Src family kinases; Subaim 2.3) To determine the genetic interactions of Crkl with Tbxl for proper development of neural crest derivatives.