Complementary and Overlapping Expression of Glial Cell Line-Derived Neurotrophic Factor (GDNF), c-ret Proto-Oncogene, and GDNF Receptor-α Indicates Multiple Mechanisms of Trophic Actions in the Adult Rat CNS

Abstract

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.

Glial Cell Line-Derived Neurotrophic Factor Alters Axon Schwann Cell Units and Promotes Myelination in Unmyelinated Nerve Fibers

“…Nevertheless, the possibility that GDNF might be acting directly on the Schwann cells remains. Schwann cells express GFR-␣1, one of the coreceptors for GDNF (Nosrat et al, 1997;Trupp et al, 1997;Bär et al, 1998). GFR-␣1 does not posses an intracellular domain; and traditionally GDNF action is thought to require the formation of the GFR-␣1 and the Ret tyrosine kinase coreceptor complex (Airaksinen et al, 1999).…”

Neurturin and Glial Cell Line-Derived Neurotrophic Factor Receptor-β (GDNFR-β), Novel Proteins Related to GDNF and GDNFR-α with Specific Cellular Patterns of Expression Suggesting Roles in the Developing and Adult Nervous System and in Peripheral Organs

“…Therefore, to complement existing studies of the distribution of the tyrosine kinase receptor RET and of GDN FR-␣ performed by us and by others (Nosrat et al, 1997;Trupp et al, 1997), we have also performed a detailed analysis of cellular expression patterns of GDNFR-␤ in the present study. We additionally compared the distribution of NTN and GDN FR-␤ mRNA with the expression of GDNF, RET, and GDN FR-␣ mRNA in adjacent tissue sections to determine the neuroanatomical and histological basis for possible interactions between GDN F and N TN with the three known receptor components.…”

“…GDN F signaling is mediated through a two-component system consisting of a glycosyl-phosphatidylinositol-linked protein termed GDN F receptor-␣ (GDNFR-␣) (Jing et al, 1996;Treanor et al, 1996), which binds GDNF, after which the GDN F-GDN FR-␣ complex binds to and activates the tyrosine kinase receptor RET (Durbec et al, 1996;Trupp et al, 1996). In situ hybridization studies of the three gene products, GDN F, RET, and GDN FR-␣, have revealed many examples in which a given set of cells expresses GDN F mRNA, whereas cells on which GDN F is assumed to act express both RET and GDN FR-␣ (Nosrat et al, 1997;Trupp et al, 1997).…”

“…For instance, GDNFR-␣ mRNA is present in brain areas such as the developing ventral striatum and the olfactory tubercle as well as in hippocampus, whereas the corresponding expressions of RET mRNA are not found (Nosrat et al, 1997). Moreover, there are instances in which RET, but not GDNFR-␣, is found in the brain such as in areas of cerebellum, the olfactory bulb, and the subthalamic nucleus (Trupp et al, 1997). These observations suggest either that the two receptor components may function independently of each other and/or that other ligands and/or receptor components exist.…”

“…In this case, the situation may be analogous to the expression by Schwann cells of the p75 NGF receptor, but not trkA, suggesting that Schwann cells produce NGF, which is secreted and binds to the p75 receptors to be presented to growing nerve fibers. Similarly, GDNF, also known to be produced by Schwann cells (Trupp et al, 1997), may be presented to nerve fibers bound to GDNFR-␣ in the cell membrane. An alternative explanation to apparent mismatches between GDNF and its receptor components requires the presence of additional gene-related products.…”