The dentate gyrus (DG) is a region of cerebral cortex in the medial temporal lobe that is frequently involved in epilepsy and other neurodevelopmental disorders. Interestingly, DG neurogenesis is extremely prolonged relative to other cortical areas, and depends on migrations of progenitor cells within the dentate migration stream (DMS) and other transient neurogenic niches. Previous studies from the PI's lab have shown that one type of cortical progenitor cells, known as intermediate progenitors (IPs) or transit-amplifying cells, specifically express Tbr2, a T-box transcription factor, during DG development as well as adult neurogenesis. New preliminary data show that Tbr2+ IPs plays major roles in transient neurogenic niches and dentate migration streams that are essential to morphogenesis of the dentate gyrus. For example, Tbr2+ IPs appear to pioneer the DMS and enhance the subsequent migration of neural stem cell (NSC)-like radial glial progenitors (RGPs).
Aims 1 and 2 of this project will analyze transient DG niches and cell migrations in mice, and determine the roles of RGPs and IPs in gyrogenesis (development of convoluted cortex).
Aim 3 extends these approaches to characterize DG malformations in mutant mice with defects of IP or radial glial progenitor (RGP) differentiation.

Public Health Relevance

The dentate gyrus (DG) is an important brain region in many neurological disorders, such as epilepsy and intellectual disability, which may result from abnormal DG growth or various forms of injury. This project will analyze fundamental mechanisms of DG development, focusing on specialized processes of neural stem cell (NSC) abventricular migration and gyrogenesis (convolution). The roles of NSCs and intermediate progenitor cells in DG development will be investigated in mice with mutations that interfere with the differentiation of each progenitor cell type.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092339-02
Application #
9233791
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02)S)
Program Officer
Lavaute, Timothy M
Project Start
2016-03-01
Project End
2020-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
$379,772
Indirect Cost
$182,897
Name
Seattle Children's Hospital
Department
Type
Independent Hospitals
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98101
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Ha, Seungshin; Tripathi, Prem P; Mihalas, Anca B et al. (2017) C-Terminal Region Truncation of RELN Disrupts an Interaction with VLDLR, Causing Abnormal Development of the Cerebral Cortex and Hippocampus. J Neurosci 37:960-971
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