Glial cell line-derived neurotrophic factor receptor α1 availability regulates glial cell line-derived neurotrophic factor signaling: evidence from mice carrying one or two mutated alleles

Abstract

Glial cell line-derived neurotrophic factor receptor α1 (GFRα1, also known as GDNFR-α) is a glycolipid-anchored membrane protein of the GFRα family, which binds glial cell line-derived neurotrophic factor [Jing S. et al. (1996) Cell 85, 1113–1124; Treanor J. J. et al. (1996) Nature 382, 80–83], a survival factor for several populations of central and peripheral neurons, including midbrain dopamine neurons [Lin L. F. et al. (1993) Science 260, 1130–1132], and mediates its ligand-induced cell response via a tyrosine kinase receptor called Ret [Takahashi M. et al. (1988) Oncogene 3, 571–578; Takahashi M. and Cooper G. M. (1987) Molec. Cell Biol. 7, 1378–1385]. In this paper, we show that mice with a null mutation of the GFRα1 gene manifest epithelial–mesenchymal interaction deficits in kidney and severe disturbances of intestinal tract development similar to those seen with glial cell line-derived neurotrophic factor or Ret null mutations. There is a marked renal dysgenesis or agenesis and the intrinsic enteric nervous system fails completely to develop. We also show that newborn GFRα1-deficient mice display no or minimal changes in dorsal root and sympathetic ganglia. This is in contrast to the deficits reported in these neuronal populations in glial cell line-derived neurotrophic factor and Ret null mutations. Mesencephalic dopaminergic neurons in the substantia nigra and ventral tegmental area appear intact at the time of birth of the mutated mice. Mice homozygous for the GFRα1 null mutation die within 24 h of birth because of uremia. Heterozygous animals, however, live to adulthood. There is a significantly reduced neuroprotective effect of glial cell line-derived neurotrophic factor in such heterozygous animals, compared with wild-type littermates, after cerebral ischemia. Taken together with previous data on glial cell line-derived neurotrophic factor and Ret, our results strongly suggest that GFRα1 is the essential GFRα receptor for signaling in the glial cell line-derived neurotrophic factor–Ret pathway in the kidney and enteric nervous system development, and that GFRα2 or GFRα3 cannot substitute for the absence of GFRα1. Moreover, neuroprotective actions of exogenous glial cell line-derived neurotrophic factor also require full GFRα1 receptor expression.