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

Glial cell line-derived neurotrophic factor receptor alpha 1 (GFR alpha 1, also known as GDNFR-alpha) is a glycolipid-anchored membrane protein of the GFR alpha family, which binds glial cell line-derived neurotrophic factor [Jing S. er al. (1996) Cell 85, 1113-1124; Treanor J. J. et nl. (1996) Natu re 382, 80-83], a survival factor for several populations of central and pe ripheral neurons, including midbrain dopamine neurons [Lin L. F. et nl. (19 93) Science 260, 1130-1132], and mediates its ligand-induced cell response via a tyrosine kinase receptor called Ret [Takahashi M. er al. (1988) Oncog ene 3, 571-578; Takahashi M. and Cooper G. M. (1987) Molec. Cell Biol, 7, 1 378-1385]. In this paper, we show that mice with a null mutation of the GFR a 1 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. The re is a marked renal dysgenesis or agenesis and the intrinsic enteric nervo us system fails completely to develop. We also show that newborn GFR alpha 1-deficient mice display no or minimal changes in dorsal root and sympathet ic ganglia. This is in contrast to the deficits reported in these neuronal populations in glial cell line-derived neurotrophic factor and Ret null mut ations. Mesencephalic dopaminergic neurons in the substantia nigra and vent ral tegmental area appear intact at the time of birth of the mutated mice. Mice homozygous for the GFR alpha 1 null mutation die within 24h of birth b ecause of uremia. Heterozygous animals, however, live to adulthood. There i s 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 f actor and Ret, our results strongly suggest that GFRa 1 is the essential GF R alpha receptor for signaling in the glial cell line-derived neurotrophic factor-Ret pathway in the kidney and enteric nervous system development, an d that GFR alpha 2 or GFR alpha 3 cannot substitute for the absence of GFR alpha 1. Moreover, neuroprotective actions of exogenous glial cell line-der ived neurotrophic factor also require full GFR alpha 1 receptor expression. Published by Elsevier Science Ltd.