The Transcription Factor Pax6 Regulates Survival of Dopaminergic Olfactory Bulb Neurons via Crystallin αA

Most neurons in the adult mammalian brain survive for the entire life of an individual. However, it is not known which transcriptional pathways regulate this survival in a healthy brain. Here, we identify a pathway regulating neuronal survival in a highly subtype-specific manner. We show that the transcription factor Pax6 expressed in dopaminergic neurons of the olfactory bulb regulates the survival of these neurons by directly controlling the expression of crystallin alpha A (Cry alpha A), which blocks apoptosis by inhibition of procaspase-3 activation. Re-expression of Cry alpha A fully rescues survival of Pax6-deficient dopaminergic interneurons in vivo and knockdown of Cry alpha A by shRNA in wild-type mice reduces the number of dopaminergic OB interneurons. Strikingly, Pax6 utilizes different DNA-binding domains for its well-known role in fate specification and this role of regulating the survival of specific neuronal subtypes in the mature, healthy brain.