脊椎动物神经系统的早期发育受到多种信号通路的调控，通过调节其下游转录因子的区域特异性表达，调控神经组织的区域分化。Shh/Gli信号主要参与神经管腹侧神经的分化，而Hox基因在后脑与脊髓的前后轴分化中具有关键作用。我们的前期研究表明，泛素连接酶RNF220的缺失会导致小鼠发育后期中后脑Hox基因的表达紊乱，脊髓腹侧神经的分化异常。初步分析表明RNF220可能通过对SMCHD1/PRC2组分EED和Gli的调节，参与对Hox基因表达和Shh信号的调控。本项目拟细致分析RNF220缺失导致的神经发育表型，并通过分子细胞生物学、遗传学方法研究RNF220在Hox基因表达与Shh信号调控的功能与作用机制。本研究对于揭示Hox基因表达和Shh信号调控的新机制将具有重要贡献。

The patterning of vertebrate nervous system during early development is governed by a group of signaling pathways, which control the regional expression of a panel of transcription factors. Sonic hedgehog (Shh) signaling through Gli is responsible for the patterning of the ventral neural tube and the Hox genes play crucial roles in the patterning of the hindbrain and spinal cord along the anterior-posterior axis. RNF220 is a RING-finger E3 ubiquitin ligase specifically expressed in the ventral part of the developing mid-hindbrain and spinal cord in both Xenopus and mouse. RNF220 knockout mouse pups were neonatal lethal. Interestingly, a group of Hox genes became abnormally activated in the hindbrainin of RNF220-/- mouse embryos, suggesting general disorder of hindbrain patterning. We have evidence that RNF220 might work through SMCHD1/EED to affect the function of the PRC2 complex, which is required to repress Hox gene expression. We also observed abnormal patterning of the ventral spinal cord in RNF220-/- mouse embryos, supporting a role of RNF220 in Shh signaling, which might be mediated by Gli proteins. In this project, we will analyze in detail the structural and functional defects of the RNF220-/- mouse hindbrain and spinal cord, and dissect the mechanisms involved in the regulation of Hox gene expression and Shh signaling.