In order to generate a functional nervous system, neural progenitors need to adopt one specific fate verses another. It is the long-term goal of my laboratory to determine the molecular mechanisms that regulate cell fate determination of neural crest and Rohon-Beard sensory neurons. Both neural crest cells and Rohon- Beard sensory neurons arise from the lateral portion of the neural plate and while neural crest cells migrate extensively to form all of the peripheral nervous system (PNS;among other derivatives), Rohon-Beard sensory neurons remain within the central nervous system (CNS). The specific objective of this application is to determine the location of the progenitor population for neural crest and RB sensory neurons, to determine whether prdml actively regulates cell proliferation and/or differentiation of neural crest and RB sensory neurons and to identify the components of the molecular pathway of prdml regulation on border cell fates. Our hypothesis is that prdml is crucial for formation of neural crest and RB sensory neurons at the lateral neural plate. A series of experiments to test this hypothesis is proposed. We propose to test the hypothesis that neural plate border progenitors are spatially segregated and restricted in their innate cell competence and their ability to respond to the environment. In addition, we will test the hypothesis that prdml acts to specify cell fate by promoting the differentiation of precursor cells at the neural plate border, without affecting cell proliferation or cell death. Lastly, we will address the hypothesis that prdml acts as a transcriptional represser to repress the target genes required for the maintenance of the precursor fate and thus promoting differentiation. Towards these goals, we will take advantage of the zebrafish system, Danio rerio, because it has well-established experimental and genetic methods make a detailed analysis of this process feasible. As an outcome of these studies, it is expected to determine that the prdml transcription factor plays critical role in the specification of neural tube and crest cells. This will be important in determining the genetic pathways that are important for neural tube and crest development, which in turn will be an important step in preventative measures in human congenital defects, such as spinal bifida and cleft lip and palate.

R01HD050698

2006-04-01

2012-01-31