Increased apoptosis of parasympathetic but not enteric neurons in mice lacking GFRα2

Enteric neurons, unlike sympathetic and sensory neurons that require target-derived neurotrophins for survival, do not undergo classical caspase-3-mediated programmed cell death (PCD) during normal development. Whether parasympathetic neurons in the pancreas, which originate from a subpopulation of enteric nervous system (ENS) precursors, or other parasympathetic neurons undergo PCD during normal mammalian development is unknown. In GFR alpha 2-deficient mice, many submandibular and intrapancreatic parasympathetic neurons are missing but whether this is due to increased neuronal death is unclear. Here we show that activated caspase-3 and PGP9.5 doubly positive neurons are present in wildtype mouse pancreas between embryonic day E15 and birth. Thus, in contrast to ENS neurons, intrapancreatic neurons undergo PCD via apoptosis during normal development. We also show that, in GFR alpha 2-deficient mice, most intrapancreatic neurons are lost during this late fetal period, which coincides with a period of increased apoptosis of the neurons. Since the percentage of BrdU and Phox2b doubly positive cells in the fetal pancreas and the number of intrapancreatic neurons at E15 were similar between the genotypes, impaired precursor proliferation and migration are unlikely to contribute to the loss of intrapancreatic neurons in GFR alpha 2-KO mice. Caspase-3-positive neurons were also found in GFR alpha 2-deficient submandibular ganglia around birth, suggesting that parasympathetic neurons depend on limited supply of (presumably target-derived neurturin) signaling via GFR alpha 2 for survival. (c) 2007 Elsevier Inc. All rights reserved.