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The Journal of Neuroscience, June 15, 1998, 18(12):4684-4696
Expression of GDNF Family Receptor Components during Development:
Implications in the Mechanisms of Interaction
Tian
Yu1,
Sheila
Scully2,
Yanbin
Yu,
Gary M.
Fox2,
Shuqian
Jing2, and
Renping
Zhou1
1 Laboratory for Cancer Research, Department of
Chemical Biology, College of Pharmacy, Rutgers University, Piscataway,
New Jersey 08855, and 2 Amgen Incorporated, Amgen Center,
Thousand Oaks, California 91320-1789
Glial cell line-derived neurotrophic factor (GDNF) and a related
factor, neurturin, promote survival of diverse groups of neurons. Both
GDNF and neurturin signal via a two-component receptor complex that
consists of a ligand-binding GDNF family receptor (GFR -1 or
GFR-2) and the receptor protein tyrosine kinase Ret. Recently, a
third receptor related to GFR-1 and GFR-2 has also been isolated
and designated GFR-3. Although much is known about the interaction
among GDNF family factors, Ret, and the -receptors in
vitro, it remains unclear about their interactions in
vivo. We show here by in situ hybridization that
Ret and the -receptors may be colocalized in the same tissues or
expressed separately in projecting and target tissues, respectively,
indicating that two distinct modes of interaction between Ret and the
-receptors exist in vivo. First, Ret may interact
with the -receptors expressed in the same cells (termed interaction
"in cis") in many tissues and cell populations that respond to GDNF
and/or neurturin, such as the substantia nigra, dorsal root ganglia,
spinal cord motoneurons, kidney, and intestine. Second, Ret may
interact with the -receptors localized in the target neurons (termed
interaction "in trans"). In addition, we present evidence in
vitro that GFR-1 mediates Ret activation by GDNF in trans.
These observations suggest that there are multiple mechanisms
regulating the interaction between Ret and the -receptors that
mediates the effects of GDNF family trophic factors on the survival and
differentiation of cells and on neuron-target interactions in the
nervous system.
Key words:
neurotrophic factors; Ret tyrosine kinase; GDNF family
receptors; neurturin; neuron-target interaction; in situ
hybridization
Copyright © 1998 Society for Neuroscience 0270-6474/98/18124684-13$05.00/0
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