Palmitoyl transferase Zdhhc21 is a candidate for the hair loss mutation dep: a potential role in epidermal homeostasis

Abstract

Palmitoylation is a post-translational modification that involves the addition of the fatty acid palmitate onto specific cysteine residues. Recently, several members of a family of transmembrane proteins containing a zinc finger and a DHHC motif, have been shown to be palmitoyl transferases in yeast and mammalian cells.The recessive hair loss mutant, dep, contains a spontaneous mutation (del-233F) at the Cterminal of Zdhhc21. Wild-type Zdhhc21 has been shown to enhance palmitoylation of several specific substrates in a transfected cell assay. Zdhhc21 localises to the cis-Golgi, whereas the mutant protein is mislocalised and is inactive in palmitoylation. We verified the candidacy of Zdhhc21 by transgenic BAC rescue.Dep is characterised by progressive hair loss, hyperplasia of the sebaceous glands, the interfollicular epidermis and the outer root sheath. In-situ hybridisation and immunohistochemistry show that both wild-type and dep mRNA and protein are present in the inner root sheath (IRS).Phenotypic characterisation using molecular markers in cell culture and on skin sections reveals abnormalities that suggest a lack of correct hair shaft differentiation in dep. We speculate that dep may have a direct or indirect effect on 4 members of the Wnt family - essential regulators of hair shaft differentiation - because of their co-expression in the IRS and because dep exhibits a Wnt-deficient phenotype.This hypothesis may provide an example of how local signalling centres may be established to allow for spatiotemporal gene expression. Furthermore, dep is the first mouse model that provides direct evidence of a function of the Dhhc family.