The cerebral cortex is the brain structure that underlies our highest cognitive and perceptual abilities. During development, proliferating cells of the cortical neuroepithelium generate young neurons that migrate away from their site of origin into distinct positions within the cortex, from which they form specific axonal connections. Defects in the production and migration of cerebral cortical neurons have fundamental implications for mental health. An increase in the size of the cerebral cortex is observed in young children with autism, and migration disorders have been implicated in schizophrenia, bipolar affective illness, epilepsy, and dyslexia. We also note that of the genes known to be mutated in X-linked mental retardation, at least six involve signaling pathways that utilize Rho family GTPases, which are implicated in neurogenesis and migration. The goals of our research are to identify molecules that regulate neurogenesis, to determine how cortical progenitors decide whether to produce neurons or more progenitors, and to characterize the mechanisms by which young neurons migrate to appropriate positions in the brain. The following questions are addressed: 1) How do cilia influence the proliferation of cortical progenitor cells? We hypothesize that the cilia regulate signaling systems that control the proliferation of neural progenitor cells. 2) How does the spatial regulation of adhesion, tension, and endocytosis contribute to neuronal migration? We propose to visualize the establishment of adhesive contacts between migrating neurons and the extracellular matrix and to explore the hypothesis that these contacts are progressively weakened by clathrin-mediated endocytosis. 3) What role do Rho family GTPases play in regulating neural progenitor proliferation and the migration of young neurons? To explore the roles of Rac1 and Cdc42 at early stages of neuronal development, we propose to use conditional genetics to ablate Cdc42 or Rac1 in the developing mouse brain and to assess the roles of these genes in the proliferation of neural progenitor cells and in neuronal migration.

Public Health Relevance

We are exploring the molecular mechanisms that control the production and migration of neurons in the cerebral cortex. An increase in the size of the cerebral cortex is observed in young children with autism, and migration disorders have been implicated in schizophrenia, bipolar affective illness, epilepsy, and dyslexia. Our studies focus in part on Rho family GTPases, which are implicated in X-linked mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH051864-18
Application #
8232105
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
1994-08-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
18
Fiscal Year
2012
Total Cost
$354,584
Indirect Cost
$131,834
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Leone, Dino P; Heavner, Whitney E; Ferenczi, Emily A et al. (2015) Satb2 Regulates the Differentiation of Both Callosal and Subcerebral Projection Neurons in the Developing Cerebral Cortex. Cereb Cortex 25:3406-19
Shieh, Jennifer C; Schaar, Bruce T; Srinivasan, Karpagam et al. (2011) Endocytosis regulates cell soma translocation and the distribution of adhesion proteins in migrating neurons. PLoS One 6:e17802
Leone, Dino P; Srinivasan, Karpagam; Brakebusch, Cord et al. (2010) The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain. Dev Neurobiol 70:659-78