During development, cMet signaling regulates a range of cellular processes, including growth, survival and migration. Human genetic studies have demonstrated a correlation between a cMET mutation and autism (Campbell et al., 2006). The cMet gene encodes a tyrosine kinase receptor, which is activated by Hgf (hepatocyte growth factor) ligand.

 In my research project I am using zebrafish as a vertebrate model system to ask how cMet signaling functions during hindbrain development. I have analyzed cMet pattern of expression in the developing zebrafish hindbrain, and found expression in rhombomere 1 (r1; future cerebellum), and in migrating facial branchiomotor neurons (FMNs). We are in the process of identifying additional hindbrain cMet-expressing neurons. Database analysis reveals two zebrafish hgf genes (hgf1 and hgf2). hgf1 is expressed at low levels throughout the developing hindbrain, and at high levels in migrating neural crest, while hgf2 is expressed in tissues surrounding the hindbrain and at midbrain hindbrain junction, suggesting a role in cerebellar development. Functional analysis using morpholino oligonucleotides shows that cMet signaling is required for normal FMNs migration and various aspects of cerebellar development.  We further find that cMet knock-down causes specific cell death, suggesting a role in cell survival. In future experiments we will expand our analysis to establish whether cMet signaling plays roles in hindbrain neural proliferation or in migration of specific cerebellar neurons.

 Together these experiments will allow us to further investigate the molecular and cellular mechanism by which cMet signaling exerts its function in the hindbrain,
and aspects of cMet function in zebrafish may inform future studies of human
autism spectrum disorders (ASD).