Positive and negative interactions of GDNF, NTN and ART in developing sensory neuron subpopulations, and their collaboration with neurotrophins

Glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN) and neu blastin/artemin (ART) are distant members of the transforming growth factor beta family, and have been shown to elicit neurotrophic effects upon sever al classes of peripheral and central neurons, Limited information from in v itro and expression studies has also substantiated a role for GDNF family l igands in mammalian somatosensory neuron development, Here, we show that al though dorsal root ganglion (DRG) sensory neurons express GDNF family recep tors embryonically, they do not survive in response to their ligands. The r egulation of survival emerges postnatally for all GDNF family ligands, GDNF and NTN support distinct subpopulations that can be separated with respect to their expression of GDNF family receptors, whereas ART supports neurons in populations that are also responsive to GDNF or NTN, Sensory neurons th at coexpress GDNF family receptors are medium sized, whereas small-caliber nociceptive cells preferentially express a single receptor, In contrast to brain-derived neurotrophic factor (BDNF)-dependent neurons, embryonic nerve growth factor (NGF)dependent nociceptive neurons switch dependency to GDNF , NTN and ART postnatally, Neurons that survive in the presence of neurotro phin 3 (NT3) or neurotrophin 4 (NT4), including proprioceptive afferents, M erkel end organs and D-hair afferents, are also supported by GDNF family li gands neonatally, although at postnatal stages they lose their dependency o n GDNF and NTN, At late postnatal stages, ART prevents survival elicited by GDNF and NTN. These data provide new insights on the roles of GDNF family ligands in sensory neuron development.