Abstract

Intermediate neurogenic progenitors (INPs) are a relatively new type of neocortical progenitor cells whose properties, daughter neuron fates, and functions in the regulation of neurogenesis remain unclear. This project will characterize molecular and cellular properties of INPs, define their contribution to cortical areas and layers, and study the regulation of INPs by intrinsic and extrinsic factors. The central hypothesis of this project is that INPs regulate not only overall neurogenesis, but also more subtle aspects of neuron differentiation such as regional identity and laminar fate. These studies will be accomplished using a variety of mouse alleles, including a novel genetic lineage tracing system to identify cortical neurons derived from INP cohorts.
The first Aim of this project is to characterize the INP transcriptome, and define proliferative and clonal properties of INPs.
The second Aim i s to determine the contribution of INP daughter neurons to cortical areas, layers, and cell types.
The third Aim i s to determine how Eomes, a transcription factor that is specifically expressed in INPs, regulates molecular and developmental properties of INPs.
The fourth Aim i s to determine how fibroblast growth factor signaling affects INP proliferation and differentiation. Together, these focused studies will provide a coherent understanding of INPs, their roles in corticogenesis, and their possible contributions to neurodevelopmental disorders and therapies. Ultimately, our understanding of diseases such as autism and intellectual disability will be advanced, as will our ability to better diagnose and treat these disorders.

Public Health Relevance

Developmental disorders of the cerebral cortex include autism, epilepsy, and intellectual disability. This project investigates basic mechanisms of cerebral cortex development, focusing on the role of intermediate neurogenic progenitors, a recently discovered progenitor type that appears to be critical in the development of cortical layers, areas, and connections.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
4R01NS085081-04
Application #
9103235
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Riddle, Robert D
Project Start
2013-09-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98101

  Publications

Dohare, Preeti; Kidwai, Ali; Kaur, Japneet et al. (2018) GSK3? Inhibition Restores Impaired Neurogenesis in Preterm Neonates With Intraventricular Hemorrhage. Cereb Cortex :
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
Elsen, Gina E; Bedogni, Francesco; Hodge, Rebecca D et al. (2018) The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6? Tbr2? Tbr1. Front Neurosci 12:571
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
Tronnes, Ashlie A; Koschnitzky, Jenna; Daza, Ray et al. (2016) Effects of Lipopolysaccharide and Progesterone Exposures on Embryonic Cerebral Cortex Development in Mice. Reprod Sci 23:771-8
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

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