Genetically separable determinants of hair keratin gene expression

The nude locus encodes Whn, a transcription factor of the forkhead/winged-helix class. Mutations in Whn cause failure of differentiation of thymic epithelium with a corresponding lack of intrathymic T-cell development; in the skin, differentiation of follicular keratinocytes is disturbed resulting, in the formation of fragile hair shafts. Here, we describe the identification and characterization of a novel nude allele, nu(StL). nu(StL) encodes a truncated Whn transcription factor protein, designated Whn(StL), lacking the activation domain but retaining the characteristic DNA binding domain. In contrast, the previously described Whn(nu) mutant protein lacks both domains. nu(StL)/nu(StL) mice show an alymphoid thymic rudiment and lack of peripheral T cells, similar to nu/nu mice. In the skin, impaired expression of hair keratin genes mHa1, mHa2, mHa3 and mHa4, mHb3, mHb4, mHb5, and mHb6 is observed in a pattern that parallels that of nu/nu mice: both mutant alleles behave as hypomorphs with respect to the expression of these hair keratin genes. However, a significant difference between these two alleles exists for mHa5 expression, which is reduced in nu(StL)/nu(StL) but not in nu/nu mice. We show that the mutant Whn protein in nu/nu mice cannot enter the nucleus, whereas the mutant Whn protein in nu(StL)/nu(StL) mice is present in the nucleus. The antimorphic characteristic of the activation-deficient Whn(StL) protein with respect to mHa5 expression is therefore most likely caused by its non-productive interaction with other proteins at cis-regulatory regions of the mHa5 gene. Our results indicate that the molecular consequences of mutations of the Whn gene can be different and demonstrate an unexpected complexity of transcriptional control mechanisms of hair keratin genes.