Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha2.
Subsets of parasympathetic and enteric neurons require neurturin signaling via glial cell line-derived neurotrophic factor family receptor alpha2 (GFRalpha2) for development and target innervation. Why GFRalpha2-deficient (Gfra2-/-) mice grow poorly has remained unclear. Here, we analyzed several factors that could contribute to the growth retardation. Neurturin mRNA was localized in the gut circular muscle. GFRalpha2 protein was expressed in most substance P-containing myenteric neurons, in most intrapancreatic neurons, and in surrounding glial cells. In the Gfra2-/- mice, density of substance P-containing myenteric ganglion cells and nerve bundles in the myenteric ganglion cell layer was significantly reduced, and transit of test material through small intestine was 25% slower compared to wild-type mice. Importantly, the knockout mice had approximately 80% fewer intrapancreatic neurons, severely impaired cholinergic innervation of the exocrine but not the endocrine pancreas, and increased fecal fat content. Vagally mediated stimulation of pancreatic secretion by 2-deoxy-glucose in vivo was virtually abolished. Retarded growth of the Gfra2-/- mice was accompanied by reduced fat mass and elevated basal metabolic rate. Moreover, the knockout mice drank more water than wild-type controls, and wet-mash feeding resulted in partial growth rescue. Taken together, the results suggest that the growth retardation in mice lacking GFRalpha2 is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility.
Rossi
Jari
J
Program in Molecular Neurobiology, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Herzig
Karl-Heinz
KH
Võikar
Vootele
V
Hiltunen
Païvi H
PH
Segerstråle
Mikael
M
Airaksinen
Matti S
MS
D000818:Animals; D005260:Female; D005769:Gastrointestinal Motility; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006130:Growth Disorders / Q000209:etiology*; D007422:Intestines / Q000294:innervation*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics; D051101:Neurturin; D009748:Nutrition Disorders / Q000209:etiology; D010179:Pancreas / Q000294:innervation; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000502:physiology*; D012463:Saliva / Q000378:metabolism; D013373:Substance P / Q000032:analysis / Q000502:physiology; D014630:Vagus Nerve / Q000502:physiology
C494991:Gfra2 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D051101:Neurturin; C495056:Nrtn protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013373:Substance P; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases