We have tested the role of glial cell line-derived neurotrophic factor
(GDNF) in regulating a group of putatively nociceptive dorsal root ga
nglion (DRG) neurons that do not express calcitonin gene-related pepti
de (CGRP) and that downregulate the nerve growth factor (NGF) receptor
tyrosine kinase, TrkA, after birth. We show that mRNA and protein for
the GDNF receptor tyrosine kinase, Ret, are expressed in the DRG in p
atterns that differ markedly from those of any of the neurotrophin rec
eptors. Most strikingly, a population of small neurons initiates expre
ssion of Ret between embryonic day 15.5 and postnatal day 7.5 and main
tains Ret expression into adulthood. These Ret-expressing small neuron
s are selectively labeled by the lectin IB4 and project to lamina Iii
of the dorsal horn. Ret-expressing neurons also express the glycosyl-p
hosphatidyl inositol-linked (GPI-linked) GDNF binding component CDNFR-
alpha and retrogradely transport I-125-GDNF, indicating the presence o
f a biologically active GDNF receptor complex. In vitro, GDNF supports
the survival of small neurons that express Ret and bind IB4 while fai
ling to support the survival of neurons expressing TrkA and CGRP. Toge
ther, our findings suggest that IB4-binding neurons switch from depend
ence on NGF in embryonic life to dependence on GDNF in postnatal life
and are likely regulated by GDNF in maturity.