Parasympathetic innervation and function of endocrine pancreas requires the glial cell line-derived factor family receptor α2 (GFRα2)

Vagal parasympathetic input to the islets of Langerhans is a regulator of islet hormone secretion, but factors promoting parasympathetic islet innervation are unknown. Neurturin signaling via glial cell line-derived neurotrophic factor family receptor alpha 2 (GFR alpha 2) has been demonstrated to be essential for the development of subsets of parasympathetic and enteric neurons. Here, we show that the parasympathetic nerve fibers and glial cells within and around the islets express GFR alpha 2 and that islet parasympathetic innervation in GFR alpha 2 knockout (KO) mice is reduced profoundly. In wild-type mice, neuroglucopenic stress produced a robust increase in plasma levels of islet hormones. In the GFR alpha 2-KO mice, however, pancreatic polypeptide and insulin responses were completely lost and glucagon response was markedly impaired. Islet morphology and sympathetic innervation, as well as basal secretions of the islet hormones, were unaffected. Moreover, a glucose tolerance test failed to reveal differences between the genotypes, indicating that direct glucose-stimulated insulin secretion was not affected by GFR alpha 2 deficiency. These results show that GFR alpha 2 signaling is needed for development of the parasympathetic islet innervation that is critical for vagally induced hormone secretion. The GFR alpha 2-KO mouse represents a useful model to study the role of parasympathetic innervation of the endocrine pancreas in glucose homeostasis.