The RAIG family member, GPRC5D, is associated with hard-keratinized structures.

Retinoic acid-inducible gene-1 was originally identified as an orphan G-protein coupled receptor induced by retinoic acid. Three highly homologous oGPCR (GPRC5B, GPRC5C, and GPRC5D) have since been classified into the RAIG1 family. We describe here, the unique tissue distribution of GPRC5D and its mechanism of expression. Hybridization in situ has shown that GPRC5D is expressed in differentiating cells that produce hard keratin, including cortical cells of the hair shaft, the keratogenous zone of the nail, and in a central region of the filiform papillae of the tongue. The GPRC5D transcript is expressed in hair follicles during mid- and late anagen, and catagen but not at telogen and early anagen phases. The differentiation-inducer, all-trans retinoic acid, induces GPRC5D expression in cultured hair bulb cells. Because the tissue distribution of GPRC5D indicates a relationship with hard keratins that constitute the major structural proteins of hard epithelial tissues, we investigated the effect of GPRC5D on acid hard keratins. Analyses of cultured cells showed that transient overexpression resulted in suppression of Ha3 and stimulation of Ha4 hair keratin gene expression. The expression was maintained in the hair follicles of whn-deficient (nude) mice, suggesting that this gene is regulated by a signal pathway different from that of hair keratin synthesis. Collectively, these data provide a framework for understanding the molecular mechanisms of GPRC5D function in hard keratinization.