The cerebral cortex is the seat for our highest cognitive and perceptual functions. Its function depends on the precise generation of different neuronal subtypes, and proper wiring of the neurons both within the cerebral cortex and between the cortex and other brain regions. Corticothalamic projection neurons extend axons into the thalamus. They are important in sensory processing, and their dysfunction has been implicated in epilepsy. Subcerebral projection neurons project axons into the midbrain, hindbrain, and spinal cord. These neurons are clinically important since they degenerate in Amyotrophic Lateral Sclerosis (ALS) and other diseases, and are damaged in spinal cord injury. Despite their functional importance and extensive involvement in neurological diseases, the molecular mechanisms regulating the generation of these neurons remain largely unknown. It was only recently discovered that Fezf2 regulates the identity and connectivity of subcerebral neurons. However, the underlying mechanism for Fezf2 function has not been determined. In addition, gene(s) regulating corticothalamic neuron identity remain undefined. Lack of such knowledge hinders our effort to understand the biological causes of various developmental and cognitive brain disorders such as ALS, spinal cord injury, mental retardation, schizophrenia, and autism, and prevents us from designing effective strategies to prevent and treat these diseases. In this grant application, we propose to determine the mechanism how the subtype identities and connectivities for subcerebral neurons (aim 1) and corticothalamic neurons (aim 2) are established during development. We will combine mouse genetics, molecular biology and neuroanatomical techniques to achieve these aims.
In aim 3, we aim to understand the lineage relationship among different neuronal subtypes in the cerebral cortex using genetic fate mapping experiments.

Public Health Relevance

The proposed research will not only provide deep insight into the mechanisms of human brain development and plasticity, but also will reveal the biological causes of various developmental and cognitive brain disorders such as ALS, spinal cord injury, mental retardation, schizophrenia, and autism. Thus results from the proposed studies will have fundamental importance in developmental biology, stem cell biology, human disease mechanisms and potential therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094589-04
Application #
8644929
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
2011-07-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$369,391
Indirect Cost
$119,391
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
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Betancourt, Jennifer; Katzman, Sol; Chen, Bin (2014) Nuclear factor one B regulates neural stem cell differentiation and axonal projection of corticofugal neurons. J Comp Neurol 522:Spc1
Betancourt, Jennifer; Katzman, Sol; Chen, Bin (2014) Nuclear factor one B regulates neural stem cell differentiation and axonal projection of corticofugal neurons. J Comp Neurol 522:6-35
Eckler, Matthew J; Chen, Bin (2014) Fez family transcription factors: controlling neurogenesis and cell fate in the developing mammalian nervous system. Bioessays 36:788-97
Kumamoto, Takuma; Toma, Ken-ichi; Gunadi et al. (2013) Foxg1 coordinates the switch from nonradially to radially migrating glutamatergic subtypes in the neocortex through spatiotemporal repression. Cell Rep 3:931-45