The migration of young neurons from sites where they are generated into the positions where they establish the circuitry of the adult brain is a critical step in development. Defects in migration cause a host of human birth defects, ranging from severe mental retardation to subtle learning disabilities, as well as a large number of the epilepsies. Our lab has focused on understanding the genes that control migration, in the hope that insights into this key step in normal development. We use the migration of the cerebellar granule neuron as a model system to examine the molecular control of glial-guided neuronal migration. The establishment of neuronal polarity is a key step in initiating neuronal migration along the glial guide. Screens for genes that function in granule neuron migration revealed high levels of expression of the polarity signaling complex mPar6a neurons exiting the cycle and establishing polarity. In C. elegans, a set of 6 PAR proteins establish anterior/posterior asymmetries and control subsequent asymmetric cell divisions. PAR proteins are conserved throughout evolution. In Preliminary Studies (Solecki et al, 2004), we discovered that the mParGa signaling complex is localized in the centrosome of migrating cerebellar granule neurons, where it coordinates the movement of the centrosome and the nucleus as the neuron migrates along the glial fiber. In the proposed research, we will study the other components of the mParGa complex, aPKC^ and Par3, in the polarity of migrating granule neurons. The role of mPartxx in cell division suggests that targeted loss of function mutants and shRNA experiments will not be feasible. We will therefore use a novel method developed by Roger Tsien to incorporate a genetic tag (TC) which binds the dye ReAshS, into mParGq and use chromophore-assisted light inactivation with a monochromatic laser to inactivate mParGa in the centrosome. For those experiments, we will generate TC-mPar6a BAG transgenic mice, enabling studies on granule cells and cortical neurons. In a final group of experiments, we will study a receptor/ligand system expressed in granule cells which interacts with the mParGa complex, the EphB ligands ephrin-B1 and ephrin-B2. Together, these experiments will provide novel information on the regulation of neuronal migration in cortical regions of developing brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051778-05
Application #
7761699
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
2006-08-02
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$406,146
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Zhu, Xiaodong; Girardo, David; Govek, Eve-Ellen et al. (2016) Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation. Neuron 89:100-12
Anne, Sandrine L; Govek, Eve-Ellen; Ayrault, Olivier et al. (2013) WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation. PLoS One 8:e81769
Roussel, Martine F; Hatten, Mary E (2011) Cerebellum development and medulloblastoma. Curr Top Dev Biol 94:235-82
Govek, Eve-Ellen; Hatten, Mary E; Van Aelst, Linda (2011) The role of Rho GTPase proteins in CNS neuronal migration. Dev Neurobiol 71:528-53
Hatten, Mary E; Roussel, Martine F (2011) Development and cancer of the cerebellum. Trends Neurosci 34:134-42
Wilson, Perrin M; Fryer, Robert H; Fang, Yin et al. (2010) Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. J Neurosci 30:8529-40
Solecki, David J; Trivedi, Niraj; Govek, Eve-Ellen et al. (2009) Myosin II motors and F-actin dynamics drive the coordinated movement of the centrosome and soma during CNS glial-guided neuronal migration. Neuron 63:63-80
Solecki, David J; Govek, Eve-Ellen; Hatten, Mary E (2006) mPar6 alpha controls neuronal migration. J Neurosci 26:10624-5