Role of endogenous retroviruses as mutagens: The hairless mutation of mice

Stoye, Jonathan P.; Fenner, Sabine; Greenoak, Gavin E.; Moran, Chris; Coffin, John M.

doi:10.1016/0092-8674(88)90201-2

Cited by 207 publications

(147 citation statements)

References 34 publications

Supporting

Mentioning

146

Contrasting

Unclassified

Order By: Relevance

“…Histology revealed that the most dynamic and most striking HF transformations in the selected reference area (dorsal thoracic midline; Figure 1C) of hr/hr skin occurred during only two days of postnatal development (on days [15][16]. Some of these HF transformations proceeded within hours and in a very narrow zone of the progressing wave of hair shedding.…”

Section: Histological Changes In Hr Mouse Skinmentioning

confidence: 99%

“…9 The hairless mutation in HRS/J mice is caused by stable integration of a modified poly-tropic retrovirus into intron 6 of the hr gene, and subsequent abnormal splicing. 15 In humans, the recessively inherited type of complete hair loss over the entire body is associated with a variety of missense, nonsense, and deletion mutations in the hr gene. 9,16 -18 Our previous study of the fully developed hairless phenotype in adult 3-to 4-month-old HRS/J hr/hr mice had suggested that the hr mutation disrupts the integrity of selected functional tissue units in most HF compartments, including the isthmus and hair bulb region as well as the dermal papilla.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

Panteleyev¹,

Botchkareva²,

Sundberg³

et al. 1999

The American Journal of Pathology

153

136

View full text Add to dashboard Cite

Mice that carry a mutation at the hairless (hr) locus develop seemingly normal hair follicles (HF) but shed their hairs completely soon after birth. Histologically , their HFs degenerate into characteristic utriculi and dermal cysts shortly after the entry of the HF into the first regression phase (catagen) , during the initiation of HF cycling. Here , we show that at least nine distinct stages of HF disintegration can be distinguished in hr/hr mice. Toward the end of HF morphogenesis (day 15 postpartum) the proximal hair bulb in hr/hr skin undergoes premature and massive apoptosis. This is associated with a dyscoordination of cell proliferation in defined HF compartments, malpositioning of the proximal inner root sheath, striking atrophy of outer root sheath , and failure of trichilemmal keratinization in the developing club hair. Rather than undergoing their normal catagenassociated involution , the hair bulb and central outer root sheath disintegrate into separate cell clusters, thus disrupting all epithelial contact with the dermal papilla. Dermal papilla fibroblasts fail to migrate upward , and break up into clusters of shrunken cells stranded in the reticular dermis as dermal cyst precursors , while the upper HF epithelium transforms into utriculi. 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. 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. This provides new insights into the pathobiology of the hr mutation , and suggests that the normal hr gene product is a crucial element of catagen control. (Am J Pathol 1999, 155:159 -171)

show abstract

Section: Histological Changes In Hr Mouse Skinmentioning

confidence: 99%

mentioning

confidence: 99%

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

Panteleyev¹,

Botchkareva²,

Sundberg³

et al. 1999

The American Journal of Pathology

153

136

View full text Add to dashboard Cite

show abstract

“…Like mutations in the gene encoding VDR, mutations in the mammalian hairless (hr) gene result in congenital hair loss in both mice (23) and humans (24,25). Remarkably, the hair loss phenotype caused by specific mutations in the human VDR gene resembles the generalized atrichia caused by mutations in the hr gene (26).…”

mentioning

confidence: 99%

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Hsieh

Sisk

Jurutka

et al. 2003

Journal of Biological Chemistry

207

201

View full text Add to dashboard Cite

Both the vitamin D receptor (VDR) and hairless (hr) genes play a role in the mammalian hair cycle, as inactivating mutations in either result in total alopecia. VDR is a nuclear receptor that functions as a ligand-activated transcription factor, whereas the hairless gene product (Hr) acts as a corepressor of both the thyroid hormone receptor (TR) and the orphan nuclear receptor, ROR␣. In the present study, we show that VDR-mediated transactivation is strikingly inhibited by coexpression of rat Hr. The repressive effect of Hr is observed on both synthetic and naturally occurring VDR-responsive promoters and also when VDR-mediated transactivation is augmented by overexpression of its heterodimeric partner, retinoid X receptor. Utilizing in vitro pull down methods, we find that Hr binds directly to VDR but insignificantly to nuclear receptors that are not functionally repressed by Hr. Coimmunoprecipitation data demonstrate that Hr and VDR associate in a cellular milieu, suggesting in vivo interaction. The Hr contact site in human VDR is localized to the central portion of the ligand binding domain, a known corepressor docking region in other nuclear receptors separate from the activation function-2 domain. Coimmunoprecipitation and functional studies of Hr deletants reveal that VDR contacts a C-terminal region of Hr that includes motifs required for TR and ROR␣ binding. Finally, in situ hybridization analysis of hr and VDR mRNAs in mouse skin demonstrates colocalization in cells of the hair follicle, consistent with a hypothesized intracellular interaction between these proteins to repress VDR target gene expression, in vivo.Nuclear receptors comprise a family of ligand-activated transcription factors that coordinate physiological and developmental processes by regulating specific changes in gene expression (1, 2). The vitamin D receptor (VDR) 1 mediates signaling by 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and is a member of the thyroid hormone/retinoic acid receptor subfamily of nuclear receptors that heterodimerize with the retinoid X receptor (RXR) on direct repeat hormone-responsive elements in the promoters of regulated genes (3, 4). Binding of liganded VDR⅐RXR to a vitamin D-responsive element (VDRE) in target genes such as osteocalcin, osteopontin, and vitamin D 24-hydroxylase (CYP24) is accompanied by the recruitment of coactivator proteins (5). VDR coactivators such as steroid receptor coactivator-1 (6), NCoA-62 (7), and vitamin D receptor interacting protein 205 (8) stimulate transcriptional activation by facilitating chromatin remodeling and/or attraction of RNA polymerase II. Although some unliganded nuclear receptors (thyroid hormone and retinoic acid receptors) can mediate repression through association with corepressors such as nuclear receptor corepressor (N-CoR) (9) and silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) (10), evidence suggests that VDR does not associate strongly with these corepressors (9 -12).Targeted gene deletion studies in mice (13, 14) and inactivat...

show abstract

“…The murine hr locus was originally identified as a spontaneous mutation caused by an endogenous retrovirus (12). The hr gene is expressed predominantly in skin and brain; the mutant phenotype in skin is progressive hair loss and increased susceptibility to cancer, while the neurological phenotype has not yet been described (11,13).…”

mentioning

confidence: 99%

The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

Thompson

Bottcher

1997

Proc. Natl. Acad. Sci. U.S.A.

129

106

View full text Add to dashboard Cite

Thyroid hormone is a critical mediator of central nervous system (CNS) development, acting through nuclear receptors to modulate the expression of specific genes. Transcription of the rat hairless (hr) gene is highly upregulated by thyroid hormone in the developing CNS; we show here that hr is directly induced by thyroid hormone. By identifying proteins that interact with the hr gene product (Hr), we find that Hr interacts directly and specifically with thyroid hormone receptor (TR)-the same protein that regulates its expression. Unlike previously described receptorinteracting factors, Hr associates with TR and not with retinoic acid receptors (RAR, RXR). Hr can act as a transcriptional repressor, suggesting that its interaction with TR is part of a novel autoregulatory mechanism.Many factors, both genetic and environmental, contribute to the formation and function of the mammalian central nervous system (CNS). An essential component of these processes is thyroid hormone (TH); if thyroid hormone levels are perturbed, abnormal development ensues, resulting in neurological deficits that include severe mental retardation (1-4). The effects of TH are mediated through the action of specific nuclear receptor proteins (5, 6). Thyroid hormone receptors (TR) act by binding to specific DNA sequences and subsequently activating or repressing the transcription of nearby genes in response to hormone binding (7,8). Several proteins that interact with TR and other nuclear hormone receptors, including both coactivators and corepressors, have been identified (9, 10).Although much is known about the mechanism of action of TR and other nuclear receptors, far less is known about the genes regulated by these receptors. We have shown that the rat hairless (hr) gene is highly up-regulated (Ͼ10-fold) by thyroid hormone in developing brain (11). The rapid induction (Ͻ4 hr) occurs even in the absence of protein synthesis, suggesting that hr is directly regulated by TR. Direct target genes are particularly important because such genes likely constitute the first step in the genetic program responsible for TH-mediated aspects of neural development. We show here that the upstream regulatory region of the hr gene includes a potent thyroid hormone response element (TRE), indicating that hr is indeed a direct target of TR.The murine hr locus was originally identified as a spontaneous mutation caused by an endogenous retrovirus (12). The hr gene is expressed predominantly in skin and brain; the mutant phenotype in skin is progressive hair loss and increased susceptibility to cancer, while the neurological phenotype has not yet been described (11, 13). The hr gene encodes a putative protein of approximately 127 kDa that lacks homology to known structural motifs other than a cluster of cysteine residues proposed to form a zinc finger (13). Toward defining the function of the hr gene product (Hr), we identified proteins that interact with Hr. Surprisingly, we found that Hr interacts with TR. Previously identified proteins that interact wit...

show abstract

Role of endogenous retroviruses as mutagens: The hairless mutation of mice

Cited by 207 publications

References 34 publications

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors

Contact Info

Product

Resources

About