We are interested in how nervous systems develop and are studying how asymmetric cell division, cell migration and axonal pathfinding contribute to the final form and connectivity of the Caenorhabditis elegans nervous system.
Asymmetric neuroblast divisions. Nervous systems contain many different types of neurons. One way to generate this diversity is for neuroblasts to divide asymmetrically, producing daughter cells that adopt distinct fates. We have been studying two proteins, HAM-1 and PIG-1, which function in several neuroblasts that divide to generate apoptotic cells and neural precursors. HAM-1 is novel protein that is asymmetrically distributed in these neuroblasts, and PIG-1 is a homolog of MELK, a conserved kinase that is expressed in all neural progenitors of the mouse brain. Both proteins regulate the position of the neuroblast cleavage plane and the distribution of developmental potential to daughter cells. Genetic screens have identified signaling pathways that are involved in some of the same asymmetric cell divisions that require HAM-1 and PIG-1, and we are currently testing whether these pathways regulate HAM-1 and PIG-1.
Cell and growth cone migrations. Cell migrations shape nervous system structure, and axonal growth cone migrations contribute to nervous system connectivity. To understand how these migrations are regulated, we screened for mutants with defects in migrations of the CAN and HSN neurons, cells that migrate in opposite directions along the anteroposterior (A/P) axis.
We are particularly interested in molecules that regulate migrations along the A/P axis. Our current model proposes that guidance along this axis is regulated by the activity of several signaling pathways that interact to control both direction and final destinations of migrating cells and growth cones. VAB-8, a novel kinesin-like protein that is both necessary and sufficient for posteriorly directed cell and growth cone migrations, functions globally to promote these migrations. The conserved kinase UNC-51 appears to regulate the activity of VAB-8 and a second molecule, UNC-14, by phosphorylation. Molecular genetic experiments suggest that VAB-8 promotes cell and growth cone migrations by regulating the activity of several guidance receptors. We also have found that Wnts, secreted glycoproteins that have been shown to function in several different developmental processes, promote the anterior migrations of cells and growth cones. The effects of the Wnts are mediated by Frizzled receptors and Dishevelled signaling proteins, and we are currently attempting to identify the molecules that function downstream of Dishevelled.