Disease relevance of Gfra1

• In addition, this study demonstrates expression of GDNF family receptor-alpha 3 (GFR alpha 3) mRNA in most adrenergic, but only in a minor part (5.3%) of the penis-projecting adult rat major pelvic ganglion neurons, as well as in almost half (45.6%) of the penile S1 dorsal root ganglion neurons [1].
• These data indicate that the gain-of-function MEN2B mutation does not abrogate ligand responsiveness of Ret and suggest that the presence of Ret ligand could play a role in the pathogenesis of the MEN2B syndrome [2].

High impact information on Gfra1

• GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF [3].
• Initially, a method to assess in vitro expansion of SSCs was developed by using flow cytometric analysis, and, subsequently, we found that a combination of glial cell line-derived neurotrophic factor, soluble glial cell line-derived neurotrophic factor-family receptor alpha-1 and basic fibroblast growth factor supports proliferation of rat SSCs [4].
• We have cloned the human and rat cDNA sequences of GDNFR-beta, a new gene encoding for a 464 amino acid long homologue of GDNFR-alpha, and assign the locus of this new gene to human chromosome 8p21-22 and mouse chromosome 14D3-E1 [5].
• Finally, RET and GDNFR-alpha show distinct patterns of regulated expression in the brain after kainic acid stimulation and in the sciatic nerve after nerve transection [6].
• They promote survival and neurite outgrowth through binding to specific members of the GDNF family receptor alpha (GFR alpha) and subsequent activation of the RET tyrosine kinase receptor [7].

Biological context of Gfra1

• Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS [6].
• Tissue distributions of their respective receptors, GFR alpha-1 and GFR alpha-2, reveal overlapping but distinct patterns of expression, which implies that the in vivo actions of GDNF and NTN may be different [8].
• The observation that GDNFR-alpha mRNA is localized in several brain structures that do not contain detectable levels of c-ret mRNA indicates that either GDNFR-alpha utilizes signal transduction molecules other than c-ret in these areas or that other GDNF-like ligands that utilize GDNFR-alpha as a receptor may be present [9].
• A marked enhancement of the gene expression for GDNF receptor alpha (GDNFR alpha), which is a component of GDNF receptor, was observed in DRG neurons after sciatic nerve transection, but the percentage of c-ret mRNA-expressing neurons was not changed [10].
• Up-regulation of GDNFR-alpha and c-ret mRNA in facial motor neurons following facial nerve injury in the rat [11].

Anatomical context of Gfra1

• In the brachial and sacral regions, the majority of motoneurons express Gfra1 but only a minority express Gfra2 [12].
• These results provide evidence that c-ret and GDNFR-alpha mRNA are expressed in neuronal populations involved in motor function and provides further support for GDNF as a target-derived neurotrophic for these motor neurons [9].
• In areas rostral to the substantia nigra, c-ret mRNA is not detected, whereas GDNFR-alpha is found in numerous brain structures, including the hippocampus, cortex, medial geniculate, and the medial habenula, the latter area expressing the highest levels of GDNFR-alpha mRNA in brain [9].
• As reported previously, GDNFR-alpha and c-ret mRNA are present in the substantia nigra and ventral tegmental area, regions containing GDNF-responsive dopamine neurons [9].
• It is conceivable therefore that GDNF and related factors may activate chromaffin and preganglionic Schwann cells through a GFR-alpha receptor in absence of c-Ret [13].

Associations of Gfra1 with chemical compounds

• They exert their biological effects by activating the RET tyrosine kinase in the presence of a GPI-linked coreceptor, either GFR alpha 1 (considered to be the favored coreceptor for GDNF) or GFR alpha 2 (the preferred NTN coreceptor) [12].
• GFR alpha-1/GAD co-expression was found mainly in the stratum (s) pyramidale (29-37%) and s. oriens (20-25%) [14].
• In addition, acute or chronic lithium treatments did not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity [15].

Regulatory relationships of Gfra1

• GFR alpha-1 is expressed in parvalbumin GABAergic neurons in the hippocampus [14].
• By using in situ hybridization and immunohistochemistry, we found that 19% to 37% of glutamic acid decarboxylase (GAD) expressing neurons co-expressed GFR alpha-1 in the hippocampus [14].

Other interactions of Gfra1

• Thus, spinal motoneurons are highly heterogeneous in their expression of receptors for neurotrophic factors of the GDNF family, but their differing responses to NTN are not correlated with expression levels of Gfra1 or Gfra2 [12].
• Responsiveness to neurturin of subpopulations of embryonic rat spinal motoneuron does not correlate with expression of GFR alpha 1 or GFR alpha 2 [12].
• Although GDNF, NTN and Ret mRNA levels were at the limit of detection, RNase protection assays revealed relatively high amounts of GFR alpha-1 and GFR alpha transcripts [16].

Analytical, diagnostic and therapeutic context of Gfra1

• Using in situ hybridization histochemistry this study investigated whether adult motor neurons express mRNAs encoding GDNFR-alpha and c-ret, and explored possible time-dependent changes in these mRNA species following facial nerve resection and crush injury [11].
• By RT-PCR, we found both Ret- and GFR-alpha-genes to be expressed in the cultured mesencephalic cells [17].

References