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.
