The proper control of cell migration is critical for metazoan development. Directed migration requires secreted extracellular signals that act through cell surface receptors to guide the migrations of those cells. Secreted Wnt proteins are members of a major class of extracellular signals that orient cell and tissue polarity, specify cell fates, and direct cell migrations of numerous cell types. Mutation of Wnt signaling cascade genes are associated with the development of human cancers;thus understanding how Wnt proteins act is of significant biomedical importance. C. elegans neuronal cell migration serves as an excellent model for understanding how signaling pathways modulate cell polarity and migration due to the fascile genetic manipulation of this organism and the ability to visualize directly the migrating cells. We previously identified mutations in the CAM-1 gene, which encodes a Ror type receptor tyrosine kinase (RTK) required for directing migrating cells to their proper destination. We found that CAM-1 acts, apparently as a traditional RTK, to orient neuronal polarity. We propose experiments to decipher its mechanism of action in orienting neuronal polarity. In addition, we have identified 41 new mutations that affect cell migration, including the first mutation in cfz-2, a C. elegans Frizzled receptor, which is involved in Wnt signaling. We propose to use large-scale DNA sequencing to rapidly clone at least three of our new migration genes from this screen. The identification and mechanistic understanding of the roles of these new genes will provide new insight into the processes that control cell migration.
Regulated cell migration is critical for normal development, including in humans. Abnormal cell migration can lead to a host of different developmental disorders including Hirschsprung disease, an intestinal disorder, lissencephaly and Kallman syndrome, two brain developmental disorders, and congenital heart defects. In addition, inappropriate migration is a hallmark of many forms of cancer.
|Craft, Teresa R; Forrester, Wayne C (2017) The Caenorhabditis elegans matrix non-peptidase MNP-1 is required for neuronal cell migration and interacts with the Ror receptor tyrosine kinase CAM-1. Dev Biol 424:18-27|