This application is an integral part of a career commitment by the applicant to understand how the diverse types of neurons found in the mammalian nervous system are generated and maintained throughout life. We currently study DNA-binding transcription factors that serve as switching molecules in the nervous system, specifically Brn-3.0, described extensively in our previous work, indicates a role in the terminal differentiation and maintenance of specific neurons in the CNS and peripheral sensory system. Unlike many transcription factors expressed in development, Brn-3.0 persists into adulthood but its role in the mature brain is unknown. We have also cloned and paretically characterized regulatory elements in Brn-3.0 genomic locus. Work elsewhere has shown that targeted disruption of Brn-3.0 in mice results in neonatal death and loss of neurons in the sensory ganglia and some CNS nuclei which express this factor. One model for this neuronal loss is a failure of Brn-3.0(-/-) neurons to respond to neurotrophins which are necessary for survival.
The Specific Aims of this application are: (1) Specifically express an axonal marker protein, tau-beta-gal, by homogous recombination at the Brn-3.0 gene locus (""""""""knock-in""""""""), allowing the normal axonal projections of the Brn-3.0 neurons to be traced in tau-beta-gal heterozygous mice. (2) Examine homozygous tau-beta-gal expressing animals which are null mutants for Brn-3.0 to allow determination of the extent of development and axonal projection of these neurons prior to cell death. (3) Examine the expression of Brn-3.0 message and protein, including the number of Brn-3.0 expressing neurons and magnitude of Brn-3.0 expression, in mature and senescent mice.
