UC San Diego

A key requirement of normal brain development is that during their proliferation, migration and differentiation precursors and daughter neurons establish and maintain a specific cell polarity, defined as having one or more axes of symmetry. Cell polarization divides the cell into different functional domains and facilitates the orientation of neurons within the overall brain framework, allowing functional connections to be established. In this dissertation I will describe work I have performed to address the question of how cell polarity is regulated during neuron migration and differentiation. I will address how the cytoskeleton and cell polarity are dynamically regulated in migrating neurons of the embryonic and adult forebrain. Specifically, I will investigate how the position of the centrosome is regulated in response to guidance cues in tangentially migrating neurons. To visualize the centrosome I have generated a transgenic mouse line that expresses a GFP- tagged centrosomal protein. In vitro studies were conducted using tangentially migrating neurons from postnatal transgenic mice to determine what molecules regulate the centrosome's position. I found that the polarity molecules GSK-3[Beta] and aPKC[Xi] regulate the centrosome's position and that repolarization in response to guidance cues depends the activity of these factors. Additionally, I analyze centrosomal position during radial migration in the embryonic cortex and report on the effect of disrupting polarity factors during migration. Next I report on the role of the microtubule-associated protein Doublecortin (DCX) in tangentially migrating neurons and show that loss of DCX results in inefficient consolidation of a single leading process during migration. Lastly, I show that during radial migration in embryogenesis, DCX cooperates with its gene-family member DCK1 to exit the multipolar stage of migration and assume a bipolar morphology