The long-term goal of my laboratory is to elucidate the mechanisms that control the development of the neocortex and defects in this process that cause disease. We propose here to study the function of members of the cadherin superfamily in neocortical development. Our preliminary data show that several members of the cadherin superfamily are expressed in a spatio-temporal pattern consistent with a role in neocortical development. Our functional data provide evidence that cadherins have a role in regulating migration. Based on these findings, we hypothesize that several members of the cadherin superfamily cooperate to regulate cell migration during neocortical development. To test our hypothesis, we will: (i) Define the expression pattern and subcellular distribution of cadherin family members in the developing neocortex;(ii) Define the function of these cadherins for cell migration using both RNA interference and mouse genetics;(iii) define the cadherin ligand binding properties;(iv) identify the signaling pathways by which these cadherins regulate the motility of cortical neurons. We anticipate that our findings will demonstrate that cadherins are central for mediating cell-cell interactions during the formation of neocortical cell layers, and that their function is regulated by other molecules that have been implicated in neocortical development such as cdk5, doublecortin and reelin. As mutations and polymorphisms in human cadherin genes have been linked to epilepsy, mental retardation, Autism Spectrum Disorder and Alzheimer disease, we anticipate that our findings will be relevant to understanding disease mechanisms.

Public Health Relevance

Disruption of the laminar architecture of the neocortex is associated with more than 25 neurological disorders, including epilepsy, schizophrenia, autism and mental retardation. Cortical layers are established by the migration of neurons from proliferative zones into the developing cortical wall and their incorporation into neuronal circuits. We propose here to identify and study cell surface receptors that control neuronal migration during the formation of cortical cell layers. We anticipate that knowledge of how these receptors control migration will be relevant for understanding the mechanisms leading to pathological changes associated with several neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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Scripps Research Institute
La Jolla
United States
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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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