SPECIFICITY OF NOTCH SIGNALING IN FEATHER DEVELOPMENT

Notch信号通路是高度保守的，并且在胚胎发生期间用于许多细胞命运决定。本文提出的研究将解决Notch 1和Notch 2如何在体内不同地发出信号，以影响细胞命运决定和发育羽毛领域的模式。将通过检查激活的Notch 1和Notch 2的异位表达（通过逆转录病毒介导的基因转移）对Notch信号通路中已知基因的表达和芽发育的影响来研究该查询。初步数据表明，Notch 1介导的羽毛促进信号和Notch 2介导的抑制信号在早期芽和芽间命运的决定。将在发育的芽中确定Notch信号传导途径组分的野生型表达模式。Notch信号传导途径中效应基因的显性负性和活化形式将用于区分Notch 1和Notch 2信号传导途径。将进行结构域交换实验以确定Notch 1和Notch 2受体的哪一部分有助于信号传导特异性，所述信号传导特异性差异地影响芽发育中的细胞命运决定。导致组成性信号传导的所有四种脊椎动物Notch受体中的突变在肿瘤过程中起因果作用。因此，研究组成型激活的Notch 1和Notch 2受体在生物学背景下的信号通路，如本提案所述，将导致更好地理解其在肿瘤发生中的潜在作用。

The Notch signaling pathway is highly conserved and is used in numerous cell fate decisions during embryogenesis. The research proposed here will address how Notch 1 and Notch2 signal differently in vivo to affect cell fate decisions and patterning in the developing feather field. This query will be investigated by examining the effects of ectopic expression of activated Notch 1 and Notch2 (by retroviral mediated gene transfer) on the expression of known genes in the Notch signaling pathway and bud development. Preliminary data indicate that Notch 1 mediates a feather promotion signal and Notch2 mediates an inhibitory signal during early bud and interbud fate decisions. Wild-type expression patterns of Notch signaling pathway components will be determined in the developing bud. Dominant negative and activated forms of effector genes in the Notch signaling pathway will be used to distinguish the Notch 1 and Notch2 signaling pathways. Domain swap experiments will be done to determine which part of the Notch 1 and Notch2 receptors contribute to the signaling specificity that differentially affects cell fate decisions in bud development. Mutations in all four vertebrate Notch receptors leading to constitutive signaling play a causal role in neoplastic processes. Therefore, the study of signaling pathways by constitutively activated Notch 1 and Notch2 receptors in a biological context, as outlined in this proposal, will lead to a better understanding of their underlying role in tumorigenesis.