Genetically separable determinants of hair keratin gene expression

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• The nude locus encodes the Whn transcription factor, crucial for thymic epithelium differentiation and T-cell development.
• Mutations in Whn lead to impaired thymic T-cell development and defective hair shaft formation.
• Previous studies identified Whn(nu) mutant protein lacking DNA binding and activation domains.

Purpose of the Study:

• To identify and characterize a novel nude allele, nu(StL).
• To investigate the molecular mechanisms underlying the distinct phenotypes observed in nu(StL)/nu(StL) mice compared to nu/nu mice.
• To elucidate the role of Whn domains in transcriptional regulation of hair keratin genes.

Main Methods:

• Characterization of the novel nude allele, nu(StL).
• Analysis of Whn protein truncation and domain retention in mutant alleles.
• Phenotypic analysis of nu(StL)/nu(StL) mice, including thymic development and peripheral T-cell populations.
• Assessment of hair keratin gene expression in mutant mice.
• Subcellular localization studies of mutant Whn proteins.

Main Results:

• The nu(StL) allele encodes a truncated Whn protein (Whn(StL)) lacking the activation domain but retaining the DNA binding domain.
• nu(StL)/nu(StL) mice exhibit an alymphoid thymus and lack peripheral T cells, similar to nu/nu mice.
• Both nu(StL) and nu/nu alleles act as hypomorphs for most hair keratin genes (mHa1-4, mHb3-6).
• A unique phenotype for nu(StL)/nu(StL) mice is the reduced expression of mHa5, not observed in nu/nu mice.
• Mutant Whn protein in nu/nu mice is excluded from the nucleus, while Whn(StL) is nuclear.
• Whn(StL) exhibits an antimorphic effect on mHa5 expression, likely due to non-productive interactions at cis-regulatory regions.

Conclusions:

• The molecular consequences of Whn gene mutations can vary significantly based on the specific mutation.
• The Whn(StL) protein's nuclear localization and retained DNA binding domain contribute to its distinct effects on gene expression.
• Transcriptional control of hair keratin genes, particularly mHa5, involves complex interactions and mechanisms beyond simple activation or binding.
• This study highlights the intricate regulation of hair keratin gene expression and the functional importance of different Whn protein domains.