Nervous systems contain many different cell types. One way to generate this diversity is for neuroblasts to divide asymmetrically, producing daughter cells that adopt distinct fates. We have identified several proteins that function in specific neuroblasts that divide asymmetrically to generate an apoptotic cell and a neuron or neural precursor. These proteins regulate the position of the neuroblast spindle and the distribution of developmental potential to daughter cells. Our current focus is to understand how Frizzleds, cell surface receptors for Wnt glycoproteins, orient these divisions and how membrane trafficking events regulate the function of Frizzled receptors.
When neurons are born, they often migrate to new positions where they differentiate. These migrations shape nervous system structure. Once in their final positions, neurons polarize and extend an axonal growth cone that navigates to reach its synaptic targets. The establishment of polarity and the ability of axons to find their targets are essential steps in establishing the connections between neurons that underlies behavior. We are studying molecules that orient the polarity and guide the migrations of these neurons and their growth cones along the C. elegans anterior/posterior (A/P) axis.
Polarity and guidance along the A/P axis appears to be regulated by the activity of several molecules that interact to orient neuronal polarity and guide migrating cells and growth cones. VAB-8, a novel kinesin-like protein orients polarity of neurons toward the posterior and promotes directed cell and growth cone migrations toward the posterior of the animal. VAB-8, acting with the conserved Rac exchange factor UNC-73/Trio, increases levels of the receptors that promote posterior polarity and guidance. We are particularly interested in defining the mechanism of how VAB-8L and UNC-73 control the levels and distributions of these receptors.
Wnts, secreted glycoproteins that function in several different developmental processes, act antagonistically to VAB-8, orienting the polarity of neurons toward the anterior and guiding the anterior migrations of C. elegans cells and growth cones. The effects of the Wnts are mediated by Frizzled receptors. Wnts and Frizzleds also act to guide growth cones along the mammalian spinal cord, but how Frizzled receptors transduce their signals in neuronal polarity and axon guidance is unclear. We are using genetic approaches to define these intracellular signaling pathways.
In C. elegans, growth cones extend along specific axons to generate highly ordered nerve bundles or fascicles. We have recently begun a project to develop methods to detect these specific axon-axon interactions and to perturb specific interactions using RNA interference techniques. Our goal is to understand how nerves develop.