The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease

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Abstract
The RET (rearranged during transfection) proto‐oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome, and Hirschsprung disease (HSCR), a developmental defect of enteric neurons. We report here that the expression of RET receptor induces apoptosis. This pro‐apoptotic effect of RET is inhibited in the presence of its ligand glial cell line‐derived neurotrophic factor (GDNF). Furthermore, we present evidence that RET induces apoptosis via its own cleavage by caspases, a phenomenon allowing the liberation/exposure of a pro‐apoptotic domain of RET. In addition, we report that Hirschsprung‐associated RET mutations impair GDNF control of RET pro‐apoptotic activity. These results indicate that HSCR may result from apoptosis of RET‐expressing enteric neuroblasts.