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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS085081-02
Application #
8720087
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (02))
Program Officer
Riddle, Robert D
Project Start
2013-09-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$420,132
Indirect Cost
$203,569
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Sun, Tao; Hevner, Robert F (2014) Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat Rev Neurosci 15:217-32
Molnár, Zoltán; Kaas, Jon H; de Carlos, Juan A et al. (2014) Evolution and development of the mammalian cerebral cortex. Brain Behav Evol 83:126-39