title: Parasympathetic innervation and function of endocrine pancreas requires the glial cell line-derived factor family receptor alpha2 (GFRalpha2).
abstract: 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 alpha2 (GFRalpha2) 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 GFRalpha2 and that islet parasympathetic innervation in GFRalpha2 knockout (KO) mice is reduced profoundly. In wild-type mice, neuroglucopenic stress produced a robust increase in plasma levels of islet hormones. In the GFRalpha2-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 GFRalpha2 deficiency. These results show that GFRalpha2 signaling is needed for development of the parasympathetic islet innervation that is critical for vagally induced hormone secretion. The GFRalpha2-KO mouse represents a useful model to study the role of parasympathetic innervation of the endocrine pancreas in glucose homeostasis.
authors.affiliation: Neuroscience Center, P.O. Box 56 (Viikinkaari 4), 00014 University of Helsinki, Finland. jari.rossi@helsinki.fi
authors.forename: Jari
authors.initials: J
authors.lastname: Rossi
authors.forename: Paavo
authors.initials: P
authors.lastname: Santamäki
authors.forename: Matti S
authors.initials: MS
authors.lastname: Airaksinen
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Herzig
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D005951:Glucose Tolerance Test; D007515:Islets of Langerhans / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology*; D010191:Pancreatic Polypeptide / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014630:Vagus Nerve / Q000502:physiology
chemical_list: D001786:Blood Glucose; C494991:Gfra2 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D011518:Proto-Oncogene Proteins; D010191:Pancreatic Polypeptide; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases