Genetic analysis of cell fate specification in the mammalian dorsal spinal cord.

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Proper formation of neuronal circuits in the mammalian spinal cord first requires that neurons be reliably specified. This specification occurs during embryonic development via signals imparted to naive cells of the neural tube, directing them to become ventral (motor) or dorsal (sensory) neurons. Though we know a great deal about the signals that specify ventral neurons, large gaps remain in our understanding of dorsal neuron specification. Forward genetic screens in the mouse have revealed novel mammalian- specific mechanisms in several biological contexts, including neural tube patterning. Such screens have shown that genes required to build cilia are necessary for several signaling pathways, including Sonic hedgehog (Shh). For instance, the hennin (hnn) mutation disrupts the structure of the ciliary axoneme, resulting in abnormally short cilia. hnn mutant mice have abnormal ventral neural tube patterning due to disrupted Shh signaling. In addition, they show novel dorsal patterning defects, and my preliminary results suggest that this is due to disrupted BMP signaling in the dorsal neural tube. Since Shh signaling is repressed correctly in the dorsal neural tube of hnn mutants, I hypothesize that the cilia defect of hnn mutants disrupts BMP signaling in the dorsal neural tube, leading to the observed dorsal patterning defects. In Aim 1, I propose a series of experiments to test this hypothesis. In Aim 2, I propose a genetic screen to identify novel or unsuspected genes necessary for dorsal neuron specification. I will incorporate a GFP marker that specifically labels the dorsal neural tube to directly visualize mutations that disrupt dorsal patterning. Once mutant lines are established, I will integrate high-throughput resequencing technology to rapidly clone the genes, enabling me to focus immediately on novel genes to identify the relevant in vivo players in dorsal neural tube specification. The work proposed here has the potential to improve human health by uncovering new information about conserved signaling pathways that are involved in many developmental processes. Disruption of these pathways during embryogenesis can cause the most common class of birth defects, neural tube defects. In adults, disruption of these pathways is implicated in tumor formation and cancer. PUBLIC HEALTH RELEVANCE: Common birth defects such as spina bifida occur when the embryonic precursor to the spinal cord, the neural tube, fails to completely close. Cells in the neural tube must receive various signals from outside the neural tube in order for proper development of the spinal cord to occur. Our research will discover and study the genes in mammals that are necessary for cells to receive and respond to these critical signals.