Neuronal apoptosis linked to EgIN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer

Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EgIN3 acts downstream of c-Jun and is specifically required among the three EgIN family members for apoptosis in this setting. Moreover, EgIN3 proapoptotic activity requires SDH activity because EgIN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.