Secretin Prevents Apoptosis in the Developing Cerebellum Through Bcl-2 and Bcl-xL

Secretin (SCT) is involved in a variety of physiological processes and has been implicated in preventing apoptosis during brain development. However, little is known about the molecular mechanism underlying its neuroprotective effects. The B cell lymphoma 2 (Bcl-2) family proteins, such as Bcl-2 and Bcl-xL, determine the commitment of neurons to apoptosis. In SCT knockout mice, we found reduced transcript levels of anti-apoptotic genes Bcl-2 and Bcl-xL, but not of pro-apoptotic gene Bax, in the developing cerebellum. SCT treatment on ex vivo cultured cerebellar slices triggered a time-dependent increase of Bcl-2 and Bcl-xL expression. This SCT-induced transcriptional regulation of Bcl-2 and Bcl-xL was dependent on the cyclic AMP (cAMP) response element-binding protein (CREB), which is a key survival factor at the convergence of multiple signaling cascades. We further demonstrated that activation of CREB by SCT was mediated by cAMP/protein kinase A (PKA) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) cascades. These findings, collectively, provide an uncharacterized signaling cascade for SCT-mediated neuronal survival, in which SCT promotes the key anti-apoptotic elements Bcl-2 and Bcl-xL in the intrinsic death pathway through PKA- and ERK-regulated CREB phosphorylation.