Role of Wnt/Planar Cell Polarity Proteins in Motor Neuron Migration

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DESCRIPTION (provided by applicant): Neuronal migration is a developmental process essential to the formation of functional neural networks in the central nervous system. Defective neuronal migration is an underlying cause of human diseases such as lissencephaly and periventricular heterotopia. To better understand the mechanisms controlling neuronal migration, our laboratory studies the migration of facial branchimotor neurons (FBMNs) in the mouse brain stem. These neurons, which control jaw and facial movements, undergo a characteristic caudal migration during development. Several molecules of the Wnt/Planar Cell Polarity (PCP) pathway have been demonstrated to regulate FBMN migration in zebrafish and mouse, but most function to determine the extent of caudal migration. We have discovered that the atypical cadherin Celsr1, on the other hand, regulates the directionality of migration, since a subset of FBMNs migrates in the wrong direction in Celsr1 mutants. In the hindbrain, Celsr1 is expressed in a dynamic fashion in several tissues including the floor plate and ventricular zone, but not in FBMN cell bodies. To understand how Celsr1 regulates directionality, we will examine the effect of deleting Celsr1 function in different hindbrain segments or floor plate cells, using a Celsr1 conditional allele and tissue-specific Cre recombinase lines. Using a variety of markers, we will test various hypotheses that could explain potential FBMN migration defects in these conditional mutants. Elucidating the cellular mechanisms through which Celsr1 regulates the directionality of FBMN migration could have implications for understanding neuronal migration disorders and other types of cell movement such as metastasis, since Wnt/PCP genes are deregulated in many cancers. PUBLIC HEALTH RELEVANCE: The proposed research aims to identify how certain molecules control an important developmental process in the brain involving the movement of neurons. The failure of neurons to move properly during embryonic development can result in severe neurological diseases in humans. Before therapies for those diseases can be created and established, the mechanisms by which these molecules control neuronal movement must be better understood.