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Volume 17, Number 10,
Issue of May 15, 1997
pp. 3554-3567
Copyright ©1997 Society for Neuroscience
Complementary and Overlapping Expression of Glial Cell
Line-Derived Neurotrophic Factor (GDNF), c-ret Proto-Oncogene, and GDNF
Receptor- Indicates Multiple Mechanisms of Trophic Actions in the
Adult Rat CNS
Received Dec. 30, 1996; revised Feb. 20, 1997; accepted Feb. 25, 1997.
Miles Trupp,
Natale Belluardo,
Hiroshi Funakoshi, and
Carlos F. Ibáñez
Division of Molecular Neurobiology, Department of Neuroscience,
Karolinska Institute, 171 77 Stockholm, Sweden
Glial cell line-derived neurotrophic factor (GDNF), the most potent
trophic factor yet described for both dopaminergic neurons of the
substantia nigra and spinal motorneurons, has recently been shown to
signal through a multireceptor complex composed of a novel
glycosylphosphatidylinositol-anchored GDNF receptor- (GDNFR-) and
the receptor tyrosine kinase product of the c-ret proto-oncogene (RET).
Despite its importance, the individual expression patterns and the
relationships between domains of expression of the different components
of this trophic system are not understood. We show here by in
situ hybridization that GDNF mRNA is expressed in the normal
adult rat brain in several targets of substantia nigra neurons,
including striatum, nucleus accumbens, thalamic nuclei, olfactory
tubercle, hippocampus, cerebellum, and cingulate cortex as well as in
the internal granular cell layer of the olfactory bulb. Within the
basal ganglia we observe a pronounced segregation of regions expressing
GDNF from those expressing GDNF receptors, suggesting that within these
structures GDNF is functioning in its anticipated role as a
target-derived trophic factor. In addition, the expression of GDNF and
both GDNF receptors within the cerebellum, hippocampus, and olfactory
bulb may indicate a paracrine mode of action. Importantly, we also see
expression of RET mRNA in cellular populations within the cerebellum
and the glomerular layer of the olfactory bulb, as well as in the
subthalamic nucleus, which lack GDNFR- expression, indicating that
RET functions either independently of GDNFR- or with GDNFR-
presented in trans. Conversely, GDNFR- is widely
expressed in many regions in which RET expression is absent, suggesting
that GDNFR- may associate with additional signaling receptors.
Finally, RET and GDNFR- show distinct patterns of regulated
expression in the brain after kainic acid stimulation and in the
sciatic nerve after nerve transection. Taken together these findings
indicate that GDNF, RET, and GDNFR- utilize multiple mechanisms to
comprise physiologically relevant trophic circuits for different
neuronal populations.
Key words:
in situ hybridization;
GDNF;
ret;
GDNFR-;
mRNA regulation;
cerebellum;
olfactory;
kainate-induced activation;
sciatic nerve transection;
motorneuron regeneration
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