ANALYSIS OF FUNCTION AND EXPRESSION OF THE CHICK GPA RECEPTOR (GPAR-ALPHA) SUGGESTS MULTIPLE ROLES IN NEURONAL DEVELOPMENT

Growth promoting activity (GPA) is a chick growth factor with low homo logy to mammalian ciliary neurotrophic factor (CNTF) (47% sequence ide ntity with rat CNTF) but displays similar biological effects on neuron al development, We have isolated a chick cDNA coding for a GPA recepto r (GPAR alpha), a GPI-anchored protein that is 70% identical to hCNTFR alpha, Functional analysis revealed that GPAR alpha mediates several biological effects of both GPA and CNTF, Soluble GPAR alpha supports G PA- and CNTF-dependent survival of human TF-1 cells. In sympathetic ne urons, GPAR alpha mediates effects of both GPA and CNTF on the express ion of vasoactive intestinal peptide (VIP) as shown by the inhibition of GPA- and CNTF-mediated VIP induction upon GPAR alpha antisense RNA expression, These results demonstrate that GPAR alpha is able to media te effects of two neurokines that are only distantly related, GPAR alp ha mRNA expression is largely restricted to the nervous system and was detected in all neurons that have been shown to respond to GPA or CNT F by increased survival or differentiation, i,e, ciliary, sympathetic, sensory dorsal root, motoneurons, retinal ganglion cells and amacrine cells. Interestingly, GPAR alpha mRNA was additionally found in neuro nal populations and at developmental periods not known to be influence d by GPA or CNTF, suggesting novel functions for GPAR alpha and its li gands during neurogenesis and neuron differentiation.