Math1 is a bHLH transcription factor that functions during neurogenesis and neuronal specification, and is essential for the development of multiple neuronal lineages including granule cells in the cerebellum, sensory hair cells in the inner ear, and dl1 dorsal commissural interneurons in the spinal cord. In order to fulfill these essential functions, Math1 expression is precisely controlled both spatially and temporally, since mis-expression of Math1 leads to mis-specification of neurons and lethality. Thus, both the regulation and function of Math1 are critical for normal neural development. The goal of this proposal is to define molecular mechanisms controlling neurogenesis and neuronal specification using Math1 as a model regulatory gene. To attain this goal, multiple strategies will be pursued. First, upstream regulators of Math1 expression will be identified that function through interactions with cis-regulatory sequences in the Math1 enhancer. These regulatory genes may be important factors for initiating differentiation in neural stem/progenitor cells, and for patterning the neural tube in the dorsal/ventral axis. To understand the molecular rationale underlying neuronal differentiation and neuronal specification, genomic approaches will be used to identify targets of Math1 transcriptional activity. And finally, to understand the in vivo specificity of function elicited by the neural bHLH factors, proteins that interact with Math1 will be identified. Success in this research program will increase our understanding of molecular mechanisms involved in neural precursor proliferation, differentiation, and specification. This understanding is important for future use of neural stem cells in treating neurological disorders involving loss of neurons from disease or trauma. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048887-03
Application #
7027641
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (02))
Program Officer
Riddle, Robert D
Project Start
2004-07-01
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$352,273
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lai, Helen C; Klisch, Tiemo J; Roberts, Rene et al. (2011) In vivo neuronal subtype-specific targets of Atoh1 (Math1) in dorsal spinal cord. J Neurosci 31:10859-71
Raft, Steven; Koundakjian, Edmund J; Quinones, Herson et al. (2007) Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development. Development 134:4405-15