Cortical radial glia are neural stem cells that self renew and produce all cortical neuron cell types in an orderly sequential fashion. There is a fundamental gap in understanding the molecular mechanism that underlies the orderly production of neuronal cell types. Our overall goal is to understand the intrinsic timing mechanism that regulates cell fate transitions during cortical neurogenesis. We have identified the transcriptional regulator Prdm16 (Positive Regulatory Domain-containing 16) as being a critical component for regulating precisely timed cell fate transitions during cortical neurogenesis. Our studies of Prdm16 serve as an entry point to understanding the relevant genetic and epigenetic programs regulating the mode of radial glia cell division, and its relationship to neuronal fate potential. In this proposal we plan to utilize MARIS (Method for Analyzing RNA following Intracellular Sorting) to define the molecular programs regulated by Prdm16 in a cell type and stage specific manner. We will also determine the temporal pattern of PRDM16 binding and regulation of cis- regulatory elements during cortical neurogenesis. The finding from our studies will have a direct impact on increasing our understanding of how expression of early transcriptional programs and chromatin modifications can contribute to neurodevelopmental disorders.

Public Health Relevance

1p36 deletion syndrome is a disorder that causes severe intellectual disability. Prdm16 is one of the primary genes lost in 1p36 deletion syndrome. Understanding the function of Prdm16 during cortical development could lead to the identification of new therapeutic targets and strategies for the treatment of neurodevelopmental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102228-02
Application #
9516026
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Lavaute, Timothy M
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
Turrero GarcĂ­a, Miguel; Harwell, Corey C (2017) Radial glia in the ventral telencephalon. FEBS Lett 591:3942-3959