Developmental defects and degenerative changes that affect the central nervous system (CNS) lead to neurological disorders including dementia, epilepsy, schizophrenia, Parkinson's and Alzheimer's disease. An understanding of the mechanisms that regulate CNS development and function is expected to provide insights into the molecular pathogenesis of neurological disorders. The development and physiology of neurons is regulated by their interactions with neighboring cells and with extracellular matrix (ECM) molecules. The mechanisms by which receptors that mediate these interactions regulate neuronal development and health are poorly defined. Our long-term goal is to understand the mechanisms by which cell-cell and celI-ECM interactions regulate CNS development, maintenance, and function. We propose here to study ECM receptors of the beta1-integrin family in the CNS. We hypothesis that beta1-integrins are part of a regulatory network that controls cell cycle progression of cortical precursor cells in the CNS. To test our hypothesis, we will use genetically modified mice carrying floxed alleles, Cre, and GFP to analyze by BrdU labeling and immunohistochemistry defects in cell proliferation and differentiation of beta1 integrin-deficient CNS precursors in vivo, and after FACS sorting in vitro. Our preliminary data validate our hypothesis. They show that beta1-integrins regulate proliferation in neurogenic zones of the CNS. We expect that beta1 -integrins are part of the regulatory circuit that coordinates cell-cycle exit with differentiation and migration. The identification of the mechanisms that regulate these events is important to understand CNS development and disease progression, as well as to control the behavior of neural stem cells in order to use them as therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046456-02
Application #
6895124
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$434,056
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Martinez-Garay, Isabel; Gil-Sanz, Cristina; Franco, Santos J et al. (2016) Cadherin 2/4 signaling via PTP1B and catenins is crucial for nucleokinesis during radial neuronal migration in the neocortex. Development 143:2121-34
Gil-Sanz, Cristina; Espinosa, Ana; Fregoso, Santiago P et al. (2015) Lineage Tracing Using Cux2-Cre and Cux2-CreERT2 Mice. Neuron 86:1091-1099
Gil-Sanz, Cristina; Landeira, Bruna; Ramos, Cynthia et al. (2014) Proliferative defects and formation of a double cortex in mice lacking Mltt4 and Cdh2 in the dorsal telencephalon. J Neurosci 34:10475-87
Ka, Minhan; Jung, Eui-Man; Mueller, Ulrich et al. (2014) MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling. Dev Biol 395:4-18
Marín, Oscar; Müller, Ulrich (2014) Lineage origins of GABAergic versus glutamatergic neurons in the neocortex. Curr Opin Neurobiol 26:132-41
Gil-Sanz, Cristina; Franco, Santos J; Martinez-Garay, Isabel et al. (2013) Cajal-Retzius cells instruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues. Neuron 79:461-77
Brunne, Bianka; Franco, Santos; Bouché, Elisabeth et al. (2013) Role of the postnatal radial glial scaffold for the development of the dentate gyrus as revealed by Reelin signaling mutant mice. Glia 61:1347-63
Trotter, Justin; Lee, Gum Hwa; Kazdoba, Tatiana M et al. (2013) Dab1 is required for synaptic plasticity and associative learning. J Neurosci 33:15652-68
Franco, Santos J; Muller, Ulrich (2013) Shaping our minds: stem and progenitor cell diversity in the mammalian neocortex. Neuron 77:19-34
Franco, Santos J; Gil-Sanz, Cristina; Martinez-Garay, Isabel et al. (2012) Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 337:746-9

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