C-terminal splice variants of Gprc5b are expressed in maturing neurons and influence neurite outgrowth

Gprc5b, a retinoic acid-inducible orphan G proteincoupled receptor, is a member of the group C metabotropic glutamate receptor family. Its function is unknown. However, recent evidence suggests that it binds Frizzled Wnt receptors and may activate noncanonical Wnt signaling pathways. Here we report the discovery of a brain-enriched C-terminal splice variant of Gprc5b, Gprc5b_v2, by cDNA microarray and RT-PCR analyses. The variant appeared to have been downregulated in the brains of learning/memory-deficient p97FE65 null mice. Despite the fact that the mice had been backcrossed with the C57Bl/6J strain for more than ten generations, Gprc5b and other genes surrounding the FE65 locus on mouse chromosome 7 were retained from the 129-derived ES cells used to generate the knockout line. The differential splicing is unlikely due to FE65 function, as originally suspected, as Gprc5b_v2 expression is also downregulated in the brains of 129/Sv substrains in comparison to C57Bl/6J mice. Further characterization revealed the expression of both Gprc5b_v2 and the previously described variant, Gprc5b_v1, in neurons. Interestingly, Gprc5b_v2 mRNA levels increase with neuronal maturation, paralleling the expression of synaptic proteins involved in the regulation of synaptic plasticity. Finally, we report evidence that both Gprc5b_v2 and Gprc5b_v1 regulate neurite outgrowth. These results are consistent with a putative function of Gprc5b in noncanonical Wnt signaling, which play roles in the regulation of neuronal morphology, and the formation and modulation of neuronal circuitry.

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Cool BH, Chan GC, Lee L, Oshima J, Martin GM, Hu Q