The GDNF Protein FamilyGene Ablation Studies Reveal What They Really Do and How

put to rest many of these uncertainties. They There are four known members of the GDNF protein also reveal new subtleties and unexpected functions for family: glial cell line–derived neurotrophic factor (GDNF), this ligand–receptor system.All four are potent survival factors for cultured peripheral scribed the phenotype of mice that are deficient in and/or central nervous system neurons and/or can pro-GFR␣1. Much like their GDNF (Moore et al., 1996; Pichel mote kidney morphogenesis in vitro. counterparts, these mice the GDNF ligands mediate their activities through a fam-fail to develop kidneys and enteric nervous systems and ily of multicomponent receptors that are composed of die shortly after birth. In addition, the mice display small the transmembrane tyrosine kinase Ret and one of four deficits in sensory, sympathetic, and motor nuclei but glycosyl-phosphatidyl inositol– (GPI-) linked proteins, retain normal numbers of dopaminergic neurons. The designated GFR␣1–GFR␣4. According to this hypothe-observed deficits provide strong support for the idea sis, Ret is shared by all the GDNF ligand receptors and that the GFR␣s are real coreceptors for the GDNF li-functions as a signaling component, whereas the GFR␣s gands. In addition, the similarities between the Gfra1 Ϫ/Ϫ are receptor specific and act as ligand binding compo-and Gdnf Ϫ/Ϫ mice revealed that in vivo GDNF acts pri-nents. Although Ret alone does not bind any of the marily through GFR␣1, even though in vitro it can interact GDNF ligands, it is capable of modifying the interactions with multiple GFR␣/Ret complexes. between these ligands and the GFR␣s. Thus, in the ab-Further experiments with primary cultures of Gfra1 Ϫ/Ϫ sence of Ret, each GFR␣ binds only a single ligand, nodose sensory and dopaminergic neurons revealed whereas in its presence they become more promiscuous that these neurons have lost their responsiveness not and can interact with 2 (GFR␣2) or 3 (GFR␣1) GDNF only to GDNF but also to NTN (Cacalano et al., 1998). ligands (see figure). Since the examined neurons survive in the Gfra1 Ϫ/Ϫ Although in vitro biochemical assays pointed to an mice, these in vitro findings did not reflect any physiolog-essential role for GPI-linked coreceptors in signal trans-ical interactions between NTN and GFR␣1. Neverthe-duction by the transmembrane tyrosine kinase Ret, the less, they highlighted the possibility that GFR␣1 can potential in vivo role of these coreceptors and the in function as an endogenous receptor for NTN in other vivo relevance of their ligand specificity remained con-tissues. troversial. In part, …