| Popis: |
The precise molecular mechanisms by which distinct, mature neuronal phenotypes arise from a common primordium, in response to specific morphogens and signals, remains a fundamental question in neurobiology. We have discovered and characterized eight novel neuronally-expressed mammalian POU domain transcription factors. Based on the distinct spatial and temporal patterns of their expression, and their structural similarity to critical determining factors in other organ systems, we hypothesize that these POU domain factors exert essential roles in establishing specific neuronal and glial phenotypes and the patterns of connection between them. We have discovered the cognate DNA recognition elements for the three classes of neuronally-expressed POU domain factors for Brn-1, Brn-2, Tst-1, Brn-4 (Class III), and Brn-3.0, Brn-3.1, and Brn-3.2 (Class IV), revealing differential spacing and orientation between the core elements of the bipartite DNA binding motif. Genetic methods are being used to critically test our hypothesis concerning the roles of these POU domain factors in determining the generation and function of specific neuronal and glial phenotypes. Homologous recombination in embryonic stem cells will be used to generate mice null for these POU IV class genomic loci, alone and in combination. We plan to test the roles of these factors in differentiation and survival of sensory neurons in dorsal root ganglia, spinal cord, and retinal ganglion cells, and their connections. Furthermore, we plan to examine the role of the four Class III POU domain factors, Brn-1, Brn-2, Tst-1 and Brn-3 in establishing central neuronal and glial phenotypes by gene deletion. |
