Genetically separable determinants of hair keratin gene expression

The nude locus encodes Whn, a transcription factor of the forkhead/winged-h elix class. Mutations in Whn cause failure of differentiation of thymic epi thelium 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 identificati on and characterization of a novel nude allele, nu(StL). nu(StL) encodes a truncated Whn transcription factor protein, designated Whn(StL), lacking th e activation domain but retaining the characteristic DNA binding domain. In contrast;, the previously described Whn(nu) mutant protein lacks both doma ins. nu(StL)/nu(StL) mice show an alymphoid thymic rudiment and lack of per ipheral 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 i s observed in a pattern that parallels that of nu/nu mice: both mutant alle les behave as hypomorphs with respect to the expression of these hair kerat in genes. However, a significant difference between these two alleles exist s 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 n ucleus, whereas the mutant Whn protein in nu(StL)/nu(StL) mice is present i n the nucleus. The antimorphic characteristic of the activation-deficient W hn(StL) protein with respect to mHa5 expression is therefore most likely ca used by its non-productive interaction with other proteins at cis-regulator y regions of the mHa5 gene. Our results indicate that the molecular consequ ences of mutations of the Whn gene can be different and demonstrate an unex pected complexity of transcriptional control mechanisms of hair keratin gen es. (C) 2000 Wiley-Liss, Inc.