Developmental/Genetic Analysis of DiGeoge Models

描述（由申请人提供）： 我们的长期目标是确定DiGeorge/velocardiofacial综合征（DGS/VCFS）的发病机制，发展和遗传使用小鼠模型。22 ql 1.2处的杂合缺失是影响许多组织的DGS的分子基础，所述组织的正常发育依赖于神经嵴细胞。这种综合征的遗传和发育病因学是复杂的。最近发现Tbxl（定位于22q11.21的T-box基因的小鼠同源物）的单倍不足导致主动脉弓动脉的异常发育，这表明TBX 1在DiGeorge综合征中起关键作用。虽然大约90%的患者在22qll.2处具有常见的3 Mb杂合缺失，但大量的综合征患者具有在3 Mb区域内不重叠的较小缺失。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22q11.21基因CRKL（CRK-Like）的缺失，定位在3 Mb缺失区也可能有助于这种综合征。CrkL（基因符号Crkl）的纯合缺失概括了广泛的神经嵴缺陷，这些缺陷与DGS非常相似。此外，我们最近注意到在C57 BL/6同源背景中Crkl的单倍不足。为了深入了解DGS的病因以及先天性心脏病的机制，我们提出了以下具体目标：1。 探讨Crkl-1胚胎心血管缺陷的发生机制。 2.确定Crkl发挥作用的遗传途径。为了解决这些问题，我们提出了以下子目标：Subaim 1.1）检验CrkL对心血管系统的适当神经嵴贡献所必需的假设; Subaim 1.2）检验CrkL对心脏神经嵴衍生物的生长或存活所必需的假设; Subaim 2.1）确定CrkL所必需的遗传等级; Subaim 2.2）检验CrkL对心脏神经嵴衍生物的生长或存活所必需的假设。Subaim 2.2）检验CrkL参与Src家族激酶介导的信号传导途径的假设; Subaim 2.3）确定CrkL与Tbxl的遗传相互作用，以适当发育神经嵴衍生物。

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.