Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor α2

Abstract

Subsets of parasympathetic and enteric neurons require neurturin signaling via glial cell line-derived neurotrophic factor family receptor α2 (GFRα2) for development and target innervation. Why GFRα2-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. GFRα2 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 wildtype controls, and wet-mash feeding resulted in partial growth rescue. Taken together, the results suggest that the growth retardation in mice lacking GFRα2 is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility. ; E-mail: mairaksi@operoni.helsinki.fi. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: glial cell line-derived neurotrophic factor (GDNF); GDNF family receptor α1 (GFRα1); neurturin (NRTN); substance P (SP); neuronal nitric oxide synthase (nNOS); vesicular acetylcholine transporter (VAChT); tyrosine hydroxylase (TH); vasoactive intestinal peptide (VIP); acetylcholinesterase (AchE); 2-deoxy-D-glucose (2-DG); basal metabolic rate (BMR); deep muscular plexus (dmp); postnatal day 4 (P4); megaunit (MU).

Localization of cholinergic innervation and neurturin receptors in adult mouse heart and expression of the neurturin gene

“…This finding is consistent with previous reports that GFRα2 is present in glial cells located in the mucosal and muscle layers of mouse small intestine (Rossi et al 2003) and in glial cells located in several mouse pelvic organs (Wanigasekara et al 2004). Results from our doublelabeling experiments indicate that GFRα2-positive cardiac Schwann cells are associated with cholinergic and noncholinergic nerve fibers.…”

“…5d-f). Because of the identification of GFRα2 in Schwann cells in other tissues (Rossi et al 2003;Wanigasekara et al 2004), additional double-labeling experiments were performed by using antibodies to the Schwann cell marker S100 and to GFRα2. These experiments showed that Schwann cells and their processes were common in the left ventricular wall (Fig.…”

GDNF family ligand immunoreactivity in the gut of teleostean fish

“…A deficiency of NRTN or of its corresponding receptor complex GFRa2 also results in abnormalities of the enteric nervous system (ENS), which are less severe than those obtained by gdnf and its receptor ablation, such as reduced myenteric plexus innervation and abnormal gastrointestinal motility (Heuckeroth et al 1999;Rossi et al 2003).…”

Neurocristopathies

“…Another Ret ligand, neurturin (NTN), has also been implicated in HSCR [121]. The co-receptor for NTN is GFRα2 and, similar to GDNF and GFRα1, mice with mutations in Ntn or GFRα2 exhibit defects in ENS formation [122,123].…”