The sensory neurons of the dorsal root ganglia (DRG) are a heterogeneous cell population that subserve such diverse modalities as pain, temperature, touch, pressure and proprioception. Yet all of these cells derive from a common pool of neuroepithelial progenitors which emigrate from the neural tube. How is such diversity in cell phenotype established? In hereditary peripheral neuropathies, aspects of this developmental sequence go awry; intriguingly, often only specific subsets of sensory neurons are deficient. For example, Familial Dysautonomia is marked by a diminution in the sensory neurons that mediate pain and temperature. Furthermore, in adult onset peripheral neuropathies, specific subsets of DRG sensory neurons degenerate. Thus an elucidation of the critical events which comprise the development of each sensory neuron subclass is required in order to develop therapeutic strategies for targeting the specific compromised subpopulation. Both extrinsic, environmental signals and inheritable cues govern the establishment of cell phenotype. Thus the goal of this proposal is to determine the role of lineage in determining the identity of subclasses of sensory neurons in addition to identifying the extrinsic factors which regulate this process. A major outstanding question is whether there are distinct subclasses of mitotically-active progenitor cells within the nascent DRG that give rise to discrete subtypes of sensory neurons. We propose to identify and characterize the subtypes of progenitor cells resident within the DRG by conducting a lineage analysis, and to identify the extrinsic factors that regulate their proliferation, survival, and/or differentiation. Our lab has provided strong evidence for a role for neurotrophins (NT-3), CNTF, PACAP and NELL2 in regulating the proliferation and differentiation of subsets of DRG progenitor cells. However, it is evident that other extrinsic factors are operative during DRG development. Based on their prominent role in multiple systems and our preliminary investigations of their expression, we propose to determine the function of a major class of receptor tyrosine kinase family, the chick homologues of Axl/tyro3/mer family: c-eyk and rek, during DRG development using in ovo misexpression analyses. Fulfillment of these aims will enhance our understanding of the cellular and molecular mechanisms that sculpt the genesis and differentiation of discrete cell types within a neura tissue.
