Renal agenesis and the absence of enteric neurons in mice lacking GDNF

Abstract

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons and motor neurons in culture. It also protects these neurons from degeneration in vitro, and improves symptoms like Parkinson's disease induced pharmacologically in rodents and monkeys. Thus GDNF might have beneficial effects in the treatment of Parkinson's disease and amyotrophic lateral sclerosis. To examine the physiological role of GDNF in the development of the mammalian nervous system, we have generated mice defective in GDNF expression by using homologous recombination in embryonic stem cells to delete each of its two coding exons. GDNF-null mice, regardless of their targeted mutation, display complete renal agencies owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also have no enteric neurons, which probably explains the observed pyloric stenosis and dilation of their duodenum. However, ablation of the GDNF gene does not affect the differentiation and survival of dopaminergic neurons, at least during embryonic development.

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

“…GDNF binds to GDNFR-a, a glycosyl phosphatidylinositol-linked cell surface receptor, which, in turn, mediates Ret activation (Jing et al, 1996;Treanor et al, 1996). Consistent with that, mice with targeted disruption of the GDNF gene show a phenotype similar to that of RET knock-out mice (Sanchez et al, 1996).…”

Expression of RET 3′ splicing variants during human kidney development

“…In situ hybridization studies have localized RET expression to the ureteric bud in embryonic murine kidney (Pachnis et al, 1993). Consistent with RET involvement in the induction of kidney morphogenesis, the RET knockout (7/7) mouse has kidney agenesis or severe dysgenesis (Schuchardt et al, 1994(Schuchardt et al, , 1996 as do mice lacking glial cell line-derived neurotrophic factor (GDNF) which encodes the soluble portion of the RET ligand (Moore et al, 1996;Pichel et al, 1996;Sa nchez et al, 1996). RET's proposed role as a transducer of mesenchymederived signals in kidney induction is supported by the localization of GDNF expression to the metanephric mesenchyme with highest expression in early developmental stages (Durbec et al, 1996a;Hellmich et al, 1996;Trupp et al, 1996).…”

GDNF/Ret signaling and the development of the kidney

“…(27) The key role of GDNF and its receptors in kidney development was initially revealed by the targeted disruption of the Ret, GDNF and Gfra1 genes. (28)(29)(30)(31)(32)(33) Mice lacking any one of these genes had similar excretory system defects, ranging from renal agenesis, to blind ending ureters with no renal tissue, to tiny, disorganized kidney rudiments. These findings established that the GDNF signal is important to induce the outgrowth of the UB from the WD and to promote its early growth and branching.…”