USU Neuroscience

mdoughty@usuhs.mil

University College London, 1995
 
Basic-helix-loop-helix (bHLH) transcription factor regulation of cerebellar development

Understanding how the complexity and diversity of the central nervous system (CNS) is generated is a fundamental goal for researchers. However the sheer numbers and intricacy of neuronal organization within the CNS presents daunting problems for successful experimentation. While the functional organization of the cerebellum is as complicated as elsewhere in the brain, there is a simplifying structural plan that suggests the possibility of truly understanding how this part of the brain is formed. The cerebellum is composed of only eight principal neuronal cell types. Remarkably, these eight cell types are generated from only two germinative zones in the cerebellar primordium, which are defined by unique basic-helix-loop-helix (bHLH) transcription factor activities. Math1 (mouse atonal homolog 1) generates glutamatergic, excitatory granule cell interneurons and projection neurons of the deep cerebellar nuclei (DCN). Ptf1a (pancreas transcription factor 1a) generates inhibitory, γ-aminobutyric acid (GABA)ergic Purkinje cells and interneurons in the cortex and DCN. Thus both Math1 and Pft1a are principally responsible for the development of the entire cerebellum. However, the mechanism by which this occurs is yet to be understood.
The goal of my laboratory is to identify the signaling pathways by which these principal drivers generate the cerebellum. Our approach is to search for other transcription factors that contribute to the specificity of the system. Data from our laboratory suggests the pro-neural bHLH factor Neurogenin1 (Ngn1) is an additional determinant factor in the specification of GABAergic cerebellar cell subtypes. The current aims of the laboratory are to precisely map Ngn1^+ve cell fates in the cerebellum and to determine the consequences of loss of Ngn1 expression on cell fate and bHLH factor expression. We use Ngn1 mutant and Cre-flox fate mapping techniques to achieve these aims.

Traumatic Brain Injury and Neuroregeneration

Traumatic brain injury (TBI) produces rapid and long-lasting changes in gene expression that shape injury and repair responses in the brain. These responses drive increased de novo neurogenesis from neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ). My laboratory aims to characterize the transcriptional regulation and gene expression characteristics of NSPCs in mice exposed to TBI. Our hypothesis is that this will lead to the identification of a cohort of "neurogenic" genes that are dynamically regulated in response to trauma. Our rationale is that these "neurogenic" genes will include appropriate targets for epigenetic therapy to treat TBI. Epigenetic therapeutics are widely used in oncology and are attracting increased interest in the treatment of disease and injury conditions affecting the brain. The long-term goal of this project is to develop therapies that augment the brain's neuroregenerative response to TBI.

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