Cycle 3 project 2

Genetic and cellular dissection of the role of the planar cell polarity protein Vangl2 in the development of the hippocampus


PhD student: Steve Carvalho, Portugal
Home Institute: Bordeaux Neurocampus; Principle Investigator: Mireille Montcouquiol
Host Institutes:
Neuroscience Center Zürich; Principle Investigator: Esther Stoeckli
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Principle Investigator: Carlos Duarte

Executive Summary

The planar cell polarity (PCP) signalling pathway was first identified in the fruit fly Drosophila, where it controls the uniform orientation of hairs and bristles on the body, perpendicular to the apical-basal axis. If the role for epithelial apical-basal determinants in the establishment of neuronal polarity is now accepted, the importance of PCP signaling in the central nervous system has received less attention. Analyses of spontaneous mutant in mice have, however, revealed a surprisingly broad array of functions for PCP genes in the developing nervous system. PCP pathway(s) affect various aspects of CNS development, including asymmetric division, neuronal migration and cilia orientation, neuronal polarity and axon guidance, dendrite morphogenesis, synaptogenesis and higher brain functions such as learning and memory to cite a few.

Vang Gogh (vang) is one of the main so-called “core PCP genes”, along with five other genes originally identified in Drosophila. Our pioneering work has led to the identification of Vangl2 and Scrib1 as PCP genes in mammals where their mutation lead to the most severe form of neural tube defects in mice called craniorachischisis. This severe phenotype leads to early lethality in all of these mutants, which has prevented so far a clear analysis of the function of PCP signaling in the CNS in embryos and later in development. Recently, we have shown that Scrib1 is a crucial regulator of brain development and spine morphology and that, mice carrying a mutation in the Scrib1 display altered neuronal morphology and physiology. Finally, Scrib1-deficient mice exhibit enhanced learning and memory abilities and impaired social behavior, two features relevant to autistic spectrum disorders (ASD).

It is not yet demonstrated yet that PCP signaling is involved per se in psychiatric and neurologic disorders, as it is currently accepted that major disruption in PCP genes in human would lead to embryonic lethality, similar to what is seen in mice. Heterozygote mutations, however, could lead to psychiatric and neurologic disorders. Notably, Fzd3, which we have identified as a binding partner of Vangl2, has been linked to neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression or mood disorder. Recently, Scrib1 and its interactor NOS1AP have been suspected to be implicated in rare cases of autistic syndrome disorders. Thus, the neurodevelopmental hypothesis of a broad variety of psychiatric and neurologic disorders that imply abnormal circuit development, could involve several PCP genes.

Axonal guidance and synaptogenesis are clearly affected in PCP mutants. In collaboration with Esther Stoeckli, an expert in morphogens and axon guidance, we will analyze the contribution of Vangl2 in the spatial and temporal regulation of Vangl2 signaling in the establishment and plasticity of synaptic circuits, in physiological and pathophysiological conditions

To reach this goal, we will study the development, maturation and plasticity of mossy fiber synapses in the CA3 region of the hippocampus, where Vangl2 is particularly enriched during development, both in terms of structure and function. This represents an excellent model for studying the mechanisms of axonal guidance, synapse specification and subcellular segregation of glutamate receptors, during postnatal development and at a mature stage. We will also benefit from our close collaboration with Christophe Mulle in Bordeaux, a mossy fiber/GluR expert.

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