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.
| Hamburg-Shields, Emily; DiNuoscio, Gregg J; Mullin, Nathaniel K et al. (2015) Sustained ?-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes. J Pathol 235:686-97 |
