The development of the vertebrate nervous system requires the generation of a large number of different types of neurons, characterized by the specific expression of neurotransmitters and their receptors and by the formation of highly specific axonal connections. These developmental processes are regulated in part by transcription factors that bind to specific DNA sequences and activate or repress the expression of neural genes. These fundamental mechanisms, used throughout the nervous system, are relevant to understanding the developmental basis of mental disorders such as schizophrenia and autism, and congenital neurological diseases. Transcriptional regulation of neural cell fate is also directly relevant to stem cell biology and the application of regenerative medicine to diseases of the brain. In prior work using transgenic mice we have shown that the POU- homeodomain factor Brn3a is required for the proper development of sensory neurons of the trigeminal and dorsal root ganglia. Brn3a governs a program of gene expression which includes the repression of early neurogenic genes and the activation of late genes that determine sensory subtypes. We also have recently shown that the LIM-homeodomain factor Islet1 regulates a gene expression program overlapping that of Brn3a, suggesting that these two factors mediate a critical transition in sensory development from proliferation and lineage determination to terminal differentiation. Our microarray studies of sensory ganglia have implicated several other transcription factors in sensory development, one of which, Hmx1, is examined in detail in this proposal.
The Specific Aims of this project will be: 1) Further define the gene regulatory program of the sensory ganglia by examining neuronal survival, axon growth and targeting, and global gene expression in mice which are double mutants for Brn3a and Islet1, and explore epigenetic mechanisms which may restrict the activity of Brn3a and Islet1. 2) Determine the role of the homeodomain factor Hmx1 in the development of the major subdivisions of the trigeminal ganglion, and the gene expression program regulated by Hmx1. 5.

Public Health Relevance

The development of the mammalian nervous system requires the generation of a large number of different types of neurons with specialized functions, and this process is regulated in part by transcription factors which act as molecular switches by binding to DNA and turning on or off specific neuronal genes. The goal of this proposal is to determine the biological effects, regulatory targets, and mechanisms of action of specific transcription factors of the homeodomain family using developing mouse and chick embryos as model systems. These basic mechanisms are essential to understanding developmental brain disorders such as schizophrenia, autism and congenital neurological diseases, and are also important for the application of stem- cell-based regenerative medicine to diseases of the brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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Seattle Children's Hospital
United States
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