The Experts below are selected from a list of 36030 Experts worldwide ranked by ideXlab platform
Angela M Christiano - One of the best experts on this subject based on the ideXlab platform.
-
Mutations in the hairless Gene underlie APL in tHRee families of Pakistani origin.
Journal of dermatological science, 2008Co-Authors: Liv Kraemer, Muhammad Wajid, Yutaka Shimomura, Angela M ChristianoAbstract:Summary Background Atrichia with papular lesions (APL) (OMIM#209500) is a rare autosomal recessively inherited form of irreversible alopecia characterized by papular lesions of keratin-filled cysts on various regions of the body. Males and females are equally affected and present with a distinct pattern of total hair loss on scalp, axilla and body. It begins shortly after birth with the development of hair loss, and patients are normally devoid of eyelashes and eyebrows. Mutations in the hairless ( HR ) Gene have been previously shown to be responsible for APL. Objective In this study, we studied the molecular basis of APL in tHRee unrelated families of Pakistani origin. Method Molecular analysis of the HR Genes was performed on genomic DNA from probands and family members. Results DNA sequencing of the HR Gene in family A revealed a novel homozygous 2 bp deletion in exon 6 leading to a frameshift and a downstream premature termination codon in exon 8 (1782-83delAG). In family B, we identified a novel homozygous deletion of a G nucleotide at the exon 15–intron 15 boundary, termed 3097delG. Family C carries a previously reported missense mutation consisting of an A-to-G transition at nucleotide 276 resulting in the mutation N970S in exon 14. Conclusion Two mutations identified in this study are novel mutations in the HR Gene and extend the body of evidence implicating the hairless Gene family in the pathoGenesis of human skin disorders. The one previously reported mutation suggests it may represent a recurrent mutation, or alternatively, an allele that is widely dispersed around the world.
-
Nonsense mutations in the hairless Gene underlie APL in five families of Pakistani origin.
Journal of dermatological science, 2007Co-Authors: Hyunmi Kim, Liv Kraemer, Muhammad Wajid, Yutaka Shimomura, Angela M ChristianoAbstract:Summary Background Atrichia with papular lesions (APL) is a rare autosomal recessive form of inherited alopecia. Affected individuals present with a distinct pattern of total hair loss on the scalp, axilla and body shortly after birth and are essentially devoid of eyelashes and eyebrows. This form of hair loss is irreversible and the histology is consistent with an absence of mature hair follicles. In addition to total atrichia, APL patients also present with papules and follicular cysts filled with cornified material. Mutations in the Hairless ( HR ) Gene have been shown to underlie APL. Objective Here, we studied five unrelated large Pakistani families with clinical manifestations of APL. Methods Based on previous reports of HR mutations in APL, we performed direct DNA sequencing analysis. Results DNA sequencing of the HR Gene in APL patients revealed tHRee novel nonsense mutations in five unrelated families. All affected individuals were homozygous for a nonsense mutation due to C-to-T transitions at different positions in the amino acid sequence. Two families carry the mutation Q323X (CAG-TAG) in exon 3, two families harbor the mutation Q502X (CAG-TAG) in exon 6, and one family had a mutation at R940X (CGA-TGA) in exon 14. Haplotype analysis revealed that all affected individuals of both APL1 and APL16 families were homozygous for the same haplotype, and likewise, the mutation in families APL2 and APL19 was on the same haplotype. Conclusions We report tHRee novel nonsense mutations in the HR Gene in APL. Two of the newly identified mutations, Q323X and Q502X, were found to be shared between unrelated families and marker analysis confirmed an identical homozygous haplotype for APL1 and APL16, and for APL2 and APL19. These findings suggest that Q323X and Q502X did not arise independently, but instead appear to have been propagated in the population. Collectively, these findings contribute further evidence for the involvement of hairless mutations in papular atrichia.
-
Molecular and functional aspects of the hairless (HR) Gene in laboratory rodents and humans.
Experimental dermatology, 2007Co-Authors: Andrey A. Panteleyev, Ralf Paus, Wasim Ahmad, John P. Sundberg, Angela M ChristianoAbstract:For many years, hairless and rhino mouse mutants have provided a useful and extensively exploited model for studying different aspects of skin physiology, including skin aging, pharmacokinetic evaluation of drug activity and cutaneous absorption, skin carcinoGenesis, and skin toxicology. Interestingly, however, hairless and rhino mice have rarely been studied for their primary cellular defect - hairlessness - and thus, the hairless Gene itself and its physiological functions have been largely overlooked for decades. The recent identification of the human homolog of the hairless Gene on human CHRomosome 8p12 confirmed the clinical significance of the phenomenon of "hairlessness" in humans, which was predicted on the basis of similarities between hairless mice and a congenital hair disorder characterized by atrichia with papules. Mutations in the hairless Gene of mice provide instructive models for further studies of HR Gene function, and may facilitate insights into the pathophysiology of different human disorders associated with the disruption of HR Gene activity. 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. On the basis of our current understanding of hairlessness, we speculate on the putative functions of the HR Gene product in skin physiology, and particularly, in hair follicle biology.
-
Molecular basis for the rhino Yurlovo (HRrhY) phenotype: severe skin abnormalities and female reproductive defects associated with an insertion in the hairless Gene
Experimental dermatology, 2007Co-Authors: Andrey A. Panteleyev, Wasim Ahmad, A. M. Malashenko, E. L. Ignatieva, R. Paus, J. P. Sundberg, Angela M ChristianoAbstract: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. Recently, the human hairless Gene was characterized, and pathoGenetic mutations were found to be associated with a recessively inherited form atrichia with papular lesions; however, the functions of HR Gene remain unclear. Allelic mutations in the murine hairless Gene represent a potentially powerful tool to elucidate the role of the hairless Gene protein product in hair follicle physiology. In 1980, several naked animals were discovered in a breeding colony of B10.R109/Y mice maintained in the Laboratory of Experimental Biological Models (L.E.B.M., Yurlovo, Moscow District, Russia). By cross breeding with hairless HRS/J HR/HR mice, this mutation was shown to be allelic with hairless. Here, we describe the molecular basis of the HR(rhY) mutation in mice, which consists of a 13 bp insertion in exon 16 of the HR Gene. Histological evaluation of Yurlovo mouse skin revealed some differences as compared to the hairless and rhino mutations, with the formation of dermal megacysts being the most specific peculiarity of the Yurlovo mutation. These results, together with previous studies of HR(rhY)/HR(rhY) mutant mice, suggest that the rhino Yurlovo (HR(rhY)) mutation represents a third and potentially more severe variation of the hairless phenotype.
-
molecular basis of a novel rhino HR rhcHR phenotype a nonsense mutation in the mouse hairless Gene
Experimental Dermatology, 2007Co-Authors: Wasim Ahmad, Andrey A. Panteleyev, John P. Sundberg, V Hensonapollonio, Angela M ChristianoAbstract:The hairless and rhino mutations are autosomal recessive allelic mutations that map to mouse CHRomosome 14. In General, the rhino phenotype is a more severe manifestation of the hairless phenotype. In both hairless and rhino mice, the hair begins shedding in a cephalocaudal pattern within 7 days after birth, and never regrows due to a series of irreversible cellular events. The hairless mutation closely resembles the human disease known as papular atrichia (MIM 209500). Recently, this disease was linked to CHRomosome 8p12, the human homolog of hairless was cloned and mapped to the same locus, and mutations have been identified in several different families. In order to gain insight into the pathophysiology of disease in papular atrichia, we sought to utilize mouse mutations as in vivo model systems. In this study, we report the identification of a homozygous nonsense mutation in the coding region of the HR Gene in a hairless mouse captured on a chicken farm in the Midwestern United States. To reflect the place of identification of this new mutation at the HR locus, we have designated this allele HR(rhCHR) using the laboratory code CHR (CHRistiano).
Catherine C. Thompson - One of the best experts on this subject based on the ideXlab platform.
-
Hairless is a nuclear receptor corepressor essential for skin function.
Nuclear receptor signaling, 2009Co-Authors: Catherine C. ThompsonAbstract:The activity of nuclear receptors is modulated by numerous coregulatory factors. Corepressors can either mediate the ability of nuclear receptors to repress transcription, or can inhibit transactivation by nuclear receptors. As we learn more about the mechanisms of transcriptional repression, the importance of repression by nuclear receptors in development and disease has become clear. The protein encoded by the mammalian Hairless (HR) Gene was shown to be a corepressor by virtue of its functional similarity to the well-established corepressors N-CoR and SMRT. Mutation of the HR Gene results in congenital hair loss in both mice and men. Investigation of Hairless function both in vitro and in mouse models in vivo has revealed a critical role in maintaining skin and hair by regulating the differentiation of epithelial stem cells, as well as a putative role in regulating Gene expression via cHRomatin remodeling.
-
Hairless and Wnt Signaling: Allies in Epithelial Stem Cell Differentiation
Cell Cycle, 2006Co-Authors: Catherine C. Thompson, Jeanne M. Sisk, Gerard M J BeaudoinAbstract:Nuclear receptors and Wnt signaling are both important regulators of developmental and physiological processes. Recent work linking these pathways in epithelial stem cell differentiation has come from studies analyzing the in vivo function of the nuclear receptor corepressor, Hairless (HR). The HR protein has long been suspected to regulate a stem cell-mediated process, hair cycling, as mutations in the HR Gene cause hair loss in both mice and men. The discovery that the HR protein is a nuclear receptor corepressor indicated that HR function in hair cycling is by regulating Gene expression. A recent study revealed that HR represses expression of Wise, an inhibitor of Wnt signaling, leading to a model in which HR controls the timing of Wnt signaling required for hair cycling. Here we review these data, and provide new data showing that HR corepressor activity is essential for its in vivo function, and identify an additional putative Wnt inhibitor regulated by HR. This work complements previous studies demonstrating the role of Wnt signaling in epithelial stem cell differentiation.
-
hairless triggers reactivation of hair growth by promoting wnt signaling
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Gerard M J Beaudoin, Jeanne M. Sisk, Catherine C. Thompson, Pierre A CoulombeAbstract:The mammalian hair cycle involves periodic reGeneration of a tiny organ, the hair follicle, tHRough a stem-cell-mediated process. 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. Here, we demonstrate that transgenic expression of HR in progenitor keratinocytes rescues follicle reGeneration in HR(-/-) mice. We show that expression of Wise, a modulator of Wnt signaling, is repressed by HR in these cells, coincident with the timing of follicle reGeneration. This work links HR and Wnt function, providing a model in which HR regulates the precise timing of Wnt signaling required for hair follicle reGeneration.
-
The hairless Gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor
Genes & development, 2001Co-Authors: Gregory B. Potter, Gerard M J Beaudoin, Cynthia Derenzo, Joanna M. Zarach, Steve H. Chen, Catherine C. ThompsonAbstract:The mammalian hairless (HR) Gene plays a critical role in the maintenance of hair growth. Although the HR Gene has been identified, the biochemical function of its encoded protein (HR) has remained obscure. Here, we show that HR functions as a transcriptional corepressor for thyroid hormone receptors (TRs). We find that two independent regions of HR mediate TR binding and that interaction requires a cluster of hydrophobic residues similar to the binding motifs proposed for nuclear receptor corepressors (N-CoR and SMRT). Similarly, we show that HR binds to the same region of TR as known corepressors. We show that HR interacts with histone deacetylases (HDACs) and is localized to matrix-associated deacetylase (MAD) bodies, indicating that the mechanism of HR-mediated repression is likely tHRough associated HDAC activity. Thus, HR is a component of the corepressor machinery, and despite its lack of sequence identity with previously described corepressors, its mode of action is remarkably conserved. 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. The discovery that HR is a corepressor provides a molecular basis for specific hair loss syndromes in both humans and mice.
-
The product of a thyroid hormone-responsive Gene interacts with thyroid hormone receptors
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Catherine C. Thompson, Margaret C. BottcherAbstract: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 up-regulated 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 receptor-interacting 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.
Bernard Moss - One of the best experts on this subject based on the ideXlab platform.
-
Recombinant protein synthesis in Chinese hamster ovary cells using a vaccinia virus/bacteriophage T7 hybrid expression system
Journal of Biological Chemistry, 1996Co-Authors: Anna Ramsey-Ewing, Bernard MossAbstract:The vaccinia virus/bacteriophage T7 expression system was adapted to Chinese hamster ovary (CHO) cells. Vaccinia virus undergoes abortive infection in CHO cells, which is characterized by a sharp reduction in protein synthesis at the stage of viral intermediate Gene expression. We determined that expression of a T7 promoter-regulated chloramphenicol acetyltransferase Gene was at least 20 times more efficient in permissive BS-C-1 than in CHO cells. The encephalomyocarditis virus 5'-untranslated region, which confers cap-independent translatability to mRNA, stimulated recombinant protein synthesis by 10-fold in both cell lines, maintaining the advantage of the BS-C-1 cells over CHO cells. Since the cowpox virus HR Gene overcomes vaccinia virus host range restriction in CHO cells, we constructed a recombinant virus that carries an intact HR Gene in addition to the T7 RNA polymerase Gene. With this virus, synthesis of T7 RNA polymerase was enhanced and production of a recombinant protein occurred in CHO cells at the level observed in permissive cell lines. Extension of the vaccinia virus/bacteriophage T7 expression system to CHO cells should be of wide interest, as these cells have advantages for preparation of recombinant proteins in research and biotechnology.
-
restriction of vaccinia virus replication in cho cells occurs at the stage of viral intermediate protein synthesis
Virology, 1995Co-Authors: Anna L Ramseyewing, Bernard MossAbstract:Abstract Vaccinia virus (VV) and cowpox virus (CPV) differ in their abilities to replicate in Chinese hamster ovary (CHO) cells because VV has a disrupted host range ( HR ) Gene. To facilitate an examination of the molecular events associated with abortive infection of CHO cells with VV, we constructed two sets of recombinant viruses that contain a viral early promoter regulating the cat Gene encoding chloramphenicol acetyltransferase and viral intermediate or late promoters regulating the lacZ Gene encoding β-galactosidase. The first set has the disrupted HR Gene and the second set has the intact CPV homolog, allowing replication in CHO cells. Reporter chloramphenicol acetyltransferase and β-galactosidase assays demonstrated that early Gene expression was unperturbed, whereas intermediate and late Gene expression were severely inhibited under abortive conditions. Metabolic labeling studies confirmed the absence of viral late protein synthesis. The accumulation of viral DNA under abortive conditions was consistent with the synthesis of viral early proteins and established that inhibition of late protein synthesis was not primarily due to a replicative block. Analysis of steady state levels of viral mRNAs revealed substantial quantities of early and intermediate species but only very small amounts of late mRNAs under nonpermissive conditions. Despite the presence of viral intermediate mRNAs, the corresponding intermediate proteins, which function as late transcription factors, were not detected by immunoprecipitation of lysates from metabolically labeled infected CHO cells. Furthermore, when expression of lacZ was regulated by an intermediate promoter, no β-galactosidase was detected even though lacZ transcripts were present. Thus, the abortive phenotype in CHO cells can be explained by a block to translation of intermediate mRNAs which prevents the synthesis of late transcription factors.
Gerard M J Beaudoin - One of the best experts on this subject based on the ideXlab platform.
-
Hairless and Wnt Signaling: Allies in Epithelial Stem Cell Differentiation
Cell Cycle, 2006Co-Authors: Catherine C. Thompson, Jeanne M. Sisk, Gerard M J BeaudoinAbstract:Nuclear receptors and Wnt signaling are both important regulators of developmental and physiological processes. Recent work linking these pathways in epithelial stem cell differentiation has come from studies analyzing the in vivo function of the nuclear receptor corepressor, Hairless (HR). The HR protein has long been suspected to regulate a stem cell-mediated process, hair cycling, as mutations in the HR Gene cause hair loss in both mice and men. The discovery that the HR protein is a nuclear receptor corepressor indicated that HR function in hair cycling is by regulating Gene expression. A recent study revealed that HR represses expression of Wise, an inhibitor of Wnt signaling, leading to a model in which HR controls the timing of Wnt signaling required for hair cycling. Here we review these data, and provide new data showing that HR corepressor activity is essential for its in vivo function, and identify an additional putative Wnt inhibitor regulated by HR. This work complements previous studies demonstrating the role of Wnt signaling in epithelial stem cell differentiation.
-
hairless triggers reactivation of hair growth by promoting wnt signaling
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Gerard M J Beaudoin, Jeanne M. Sisk, Catherine C. Thompson, Pierre A CoulombeAbstract:The mammalian hair cycle involves periodic reGeneration of a tiny organ, the hair follicle, tHRough a stem-cell-mediated process. 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. Here, we demonstrate that transgenic expression of HR in progenitor keratinocytes rescues follicle reGeneration in HR(-/-) mice. We show that expression of Wise, a modulator of Wnt signaling, is repressed by HR in these cells, coincident with the timing of follicle reGeneration. This work links HR and Wnt function, providing a model in which HR regulates the precise timing of Wnt signaling required for hair follicle reGeneration.
-
The hairless Gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor
Genes & development, 2001Co-Authors: Gregory B. Potter, Gerard M J Beaudoin, Cynthia Derenzo, Joanna M. Zarach, Steve H. Chen, Catherine C. ThompsonAbstract:The mammalian hairless (HR) Gene plays a critical role in the maintenance of hair growth. Although the HR Gene has been identified, the biochemical function of its encoded protein (HR) has remained obscure. Here, we show that HR functions as a transcriptional corepressor for thyroid hormone receptors (TRs). We find that two independent regions of HR mediate TR binding and that interaction requires a cluster of hydrophobic residues similar to the binding motifs proposed for nuclear receptor corepressors (N-CoR and SMRT). Similarly, we show that HR binds to the same region of TR as known corepressors. We show that HR interacts with histone deacetylases (HDACs) and is localized to matrix-associated deacetylase (MAD) bodies, indicating that the mechanism of HR-mediated repression is likely tHRough associated HDAC activity. Thus, HR is a component of the corepressor machinery, and despite its lack of sequence identity with previously described corepressors, its mode of action is remarkably conserved. 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. The discovery that HR is a corepressor provides a molecular basis for specific hair loss syndromes in both humans and mice.
Thomas O Eichmann - One of the best experts on this subject based on the ideXlab platform.
-
transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock
PLOS Biology, 2018Co-Authors: Kenneth A Dyar, Michael Jean Hubert, Ashfaq Ali Mir, Stefano Ciciliot, Dominik Lutter, Franziska Greulich, Fabiana Quagliarini, Maximilian Kleinert, Katrin Fischer, Thomas O EichmannAbstract:Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-HR Gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in Gene expression and metabolite fluctuations.
-
transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock
PLOS Biology, 2018Co-Authors: Kenneth A Dyar, Michael Jean Hubert, Stefano Ciciliot, Dominik Lutter, Franziska Greulich, Fabiana Quagliarini, Maximilian Kleinert, Katrin Fischer, Thomas O Eichmann, Lauren E WrightAbstract:Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-HR Gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in Gene expression and metabolite fluctuations.