Disease relevance of Hr

• Genetic analyses showed perfect concordance between the hr phenotype and the presence of the provirus in a number of inbred and congenic strains of mice [1].
• In this study we analyzed lymphomas from six inbred mouse strains, AKR/J, C58/J, HRS/J (hr/hr and hr/+), SJL/J, SEA/GnJ, and CWD/LeAgl, to determine whether these correlations are also evident in these strains [2].
• We provide an overview of current data on the structure and expression patterns of the hr gene, and of mutations at the hairless locus in mice and humans, including the genetic basis of different alleles, the pathology of hairlessness, reproductive and immunological defects, and susceptibility to dioxin toxicity [3].
• In 1989, mice bearing mutations at the hr (hairless) locus were first proposed as a model for the human hair growth disorder papular atrichia, since in both these mice and in corresponding patients, a complete hair loss develops due to disintegration of the normal follicle structure into dermal cysts and so-called utriculi [4].
• TPH was detected in all fourteen carcinoids analyzed [Km = 185 +/- 17 microM (mean +/- SEM); Vmax = 2.4 +/- 1.2 nmol/hr/mg protein] [5].

High impact information on Hr

• Using oligonucleotide probes specific for different classes of murine leukemia virus, we have identified and cloned a provirus present in HRS/J hr/hr animals but absent in HRS/J +/+ [1].
• Here, we show that Hr functions as a transcriptional corepressor for thyroid hormone receptors (TRs) [6].
• On the basis of its thyroid hormone-inducible and tissue- and developmental-specific expression, Hr likely defines a new class of nuclear receptor corepressors that serve a more specialized role than ubiquitous corepressors [6].
• FRIP expression is significantly reduced in T cells from hr/hr mice [7].
• Disproportion in T-cell subpopulations in immunodeficient mutant hr/hr mice [8].

Biological context of Hr

• Close linkage of the chromosome 14 morphological marker hairless (hr) to Rb-1 is also implied [9].
• Toward the end of HF morphogenesis (day 15 postpartum) the proximal hair bulb in hr/hr skin undergoes premature and massive apoptosis [10].
• Thus, loss of a functional hr gene product (a putative zinc finger transcription factor) initiates a premature, highly dysregulated catagen, which results in the destruction of the normal HF architecture and abrogates the HF's ability to cycle [10].
• An immunologic analysis of mutants HRS/J mice was done comparing hr/hr homozygotes to hr/+ heterozygotes [11].
• Here, we further characterize how hairlessness develops in HRS/J hairless mouse skin (hr) by histology, histochemistry, immunohistology, and in situ hybridization [12].

Anatomical context of Hr

• The Hairless (Hr) gene encodes a nuclear receptor corepressor (HR) that is essential for hair follicle regeneration, but its role in this process is unknown [13].
• Here, we demonstrate that transgenic expression of HR in progenitor keratinocytes rescues follicle regeneration in Hr(-/-) mice [13].
• Cells from pooled lymph nodes of hr/hr mice did not show a correspondingly gross disporprotion of Ly1 and Ly123 cells [8].
• Total counts of splenic T cells, and of B cells, were not significantly different in hr/hr and +/hr mice [8].
• It is further suggested that this defect is due to an abnormality in thymus epithelium, which is also related to the high grade expression of xenotropic virus in old hr/hr thymocytes and subsequent development of leukemia [11].

Associations of Hr with chemical compounds

• AU-rich RNA-destabilizing elements (AREs) found in the 3' untranslated regions of many labile mRNAs encoding proto-oncoproteins and cytokines generally contain (i) one or more copies of the AUUUA pentanucleotide and (ii) a high content of uridylate and sometimes also adenylate residues [14].
• The effect of systemic treatment with the anti-inflammatory drug indomethacin on sun-induced skin carcinogenesis was examined in lightly pigmented hairless hr/hr C3H/Tif mice [15].
• Excision repair of pyrimidine dimers was examined at the genome overall in three strains of hairless (hr/hr) and congenic wild-type mice, as well as in the expressed H-ras gene in hairless mice [16].
• Remarkably, the specificity of Hr corepressor action can be transferred to a retinoic acid receptor by exchanging the activation function 2 (AF-2) helix [17].
• Sequence analysis of the complete cDNA of the candidate gene, hairless (Hr), identified a homozygous G-to-T transition at nucleotide 3572, leading to the substitution of glycine by tryptophan, designated Gly960Trp [18].

Co-localisations of Hr

• Most A-SMase activity in hairless mice (hr(-/-)) was found in the outer epidermal cell layers and colocalized in the lamellar bodies with A-SMase and sphingomyelin [19].

Regulatory relationships of Hr

• These changes are associated with increased expression of Hr, suggesting a role for VDR in regulating Hr expression [20].

Other interactions of Hr

• The resulting congenic line, B10.D2.C-Tcraa/Bo carries a recombination between the Tcra and the hr loci; thus, the transferred differential segment is the centromeric 18-27 cM of the BALB/c chromosome 14 [21].
• Functional characterization of a non-AUUUA AU-rich element from the c-jun proto-oncogene mRNA: evidence for a novel class of AU-rich elements [14].
• Within 24 hr of exposure to LPS, TNF-alpha levels were increased in the culture media of all cells tested [22].
• The Frl series shows no evidence of linkage with hr [23].
• Some dermal papilla cells, which normally never undergo apoptosis, also become TUNEL+ in hr/hr skin, and their normally high expression of a key adhesion molecule, neural cell adhesion molecule, declines [10].

Analytical, diagnostic and therapeutic context of Hr

• At 1 hr prior to each LPS injection (13:00 and 16:00 hours), an intraperitoneal injection of saline, b-LF, or rh-LF (1 mg/body) was administered [24].
• Levels of Hr were greater in the Vdr null mice compared to wildtype controls, results confirmed by quantitative RT-PCR [20].
• The relative amounts of Hr mRNA and HR protein determined by real-time PCR and Western blot analyses, respectively, were slightly elevated in the mutant mice [18].
• The inhibition of enzyme activity, seen after a dose of 250 mg/kg, reached a maximum 120 min after treatment and had subsided substantially 8 hr after dosing; by 24 hr. enzyme activity was fully restored [25].
• Inhibition of UVR-induced tanning and immunosuppression by topical applications of vitamins C and E to the skin of hairless (hr/hr) mice [26].

References