Molecular genetic regulation of vertebrate CNS development

我们对动物发育的理解中的一个基本问题是细胞外信号线索如何控制胚胎的形态发生和细胞命运决定。在许多动物中，分泌的Hedgehog（Hh）蛋白在发育和成年过程中发挥着关键和不同的作用。在人类和小鼠中，Sonic hedgehog（Shh）在指导模式形成和诱导许多胚胎组织中的祖细胞/干细胞分裂中具有重要作用，包括中枢神经系统（CNS）、四肢、体节、肺、肠道、牙齿和皮肤。Matise实验室和其他地方的先前工作已经证明，三个Gli转录调节因子在介导脊椎动物CNS中对Shh信号的反应中起着核心作用;然而，对此负责的转录机制知之甚少。目前的提议将使用发育中的鸡脊髓作为模型系统来解决这个问题。这些实验将扩展Matise实验室先前由NSF资助的工作，该工作证明了已鉴定的Shh-Gli靶基因的正常表达还涉及致力于介导另一种信号Wnt通路的蛋白质。与其他实验室的工作一起，这些实验定义了控制细胞命运和组织模式的共同机制，该机制涉及在基因调控水平上整合多种外部位置信号线索。（UMDNJ/罗格斯大学），有一个高度多样化的学生群体，和Matise实验室一直吸引学生谁寻求在神经科学培训，分子遗传学和发育生物学。该实验室为本科生和研究生提供了一个有吸引力的环境，并有一个优秀的历史，涉及来自代表性不足的群体的学生。该实验的实验设计和方法是非常平易近人，提供了一个理想的机会，培养学生应用强大的技术来研究重要的生物学问题。这种培训对于美国作为世界科学进步领导者的持续卓越至关重要。

A fundamental issue in our understanding of animal development is how extracellular signaling cues control morphogenesis and cell fate determination in embryos. In many animals, the secreted Hedgehog (Hh) proteins play critical and diverse roles during development and in adults. In humans and mice, Sonic hedgehog (Shh) has an important role in directing pattern formation and inducing progenitor/stem cell division in numerous embryonic tissues, including the central nervous system (CNS), limbs, somites, lungs, gut, teeth, and skin. Previous work in the Matise lab and elsewhere have demonstrated that three Gli transcriptional regulators play a central role in mediating the response to Shh signaling in the vertebrate CNS; however, the transcriptional mechanisms that are responsible for this are poorly understood.The current proposal will address this issue using the developing chicken spinal cord as a model system. The experiments will extend previous NSF-funded work in the Matise lab that demonstrated the normal expression of an identified Shh-Gli target gene also involves proteins dedicated to mediating another signal, the Wnt pathway. Taken with work from other labs, these experiments define what may be a common mechanism for controlling cell fates and tissue patterning that involves the integration of multiple extrinsic positional signaling cues at the level of gene regulation.The proposed studies will be undertaken at a university (UMDNJ/Rutgers) that has a highly diverse student population, and the Matise lab has consistently attracted students who seek training in neuroscience, molecular genetics, and developmental biology. The lab provides an attractive environment for undergraduate and graduate students, and has an excellent history of involving students from under-represented groups. The experimental design and methodology of the proposed experiments is highly approachable, providing an ideal opportunity to train students to apply powerful technologies to study important biological problems. Such training is critical to the continued pre-eminence of the U.S. as a worldwide leader in the advancement of science.