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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Lavaute, Timothy M
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Adams Waldorf, Kristina M; Nelson, Branden R; Stencel-Baerenwald, Jennifer E et al. (2018) Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 24:368-374
Mihalas, Anca B; Hevner, Robert F (2018) Clonal analysis reveals laminar fate multipotency and daughter cell apoptosis of mouse cortical intermediate progenitors. Development 145:
Kaplan, E S; Ramos-Laguna, K A; Mihalas, A B et al. (2017) Neocortical Sox9+ radial glia generate glutamatergic neurons for all layers, but lack discernible evidence of early laminar fate restriction. Neural Dev 12:14
Mihalas, A B; Hevner, R F (2017) Control of Neuronal Development by T-Box Genes in the Brain. Curr Top Dev Biol 122:279-312
Probst, Simone; Daza, Ray A; Bader, Natalie et al. (2017) A dual-fluorescence reporter in the Eomes locus for live imaging and medium-term lineage tracing. Genesis 55:
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
Mihalas, Anca B; Elsen, Gina E; Bedogni, Francesco et al. (2016) Intermediate Progenitor Cohorts Differentially Generate Cortical Layers and Require Tbr2 for Timely Acquisition of Neuronal Subtype Identity. Cell Rep 16:92-105
Hevner, Robert F (2016) Evolution of the mammalian dentate gyrus. J Comp Neurol 524:578-94