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1.
Proc Natl Acad Sci U S A ; 121(9): e2320129121, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38377195

RESUMO

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.


Assuntos
Proteínas de Ligação a DNA , Proteínas Repressoras , Humanos , Feminino , Masculino , Animais , Camundongos , Proteínas de Ligação a DNA/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Correpressoras/genética , Correpressor 2 de Receptor Nuclear/genética , Tretinoína/farmacologia , Anticoncepção , Correpressor 1 de Receptor Nuclear
2.
Proc Natl Acad Sci U S A ; 115(41): 10381-10386, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30254164

RESUMO

Nuclear hormone receptors (NRs), such as retinoic acid receptors (RARs), play critical roles in vertebrate development and homeostasis by regulating target gene transcription. Their activity is controlled by ligand-dependent release of corepressors and subsequent recruitment of coactivators, but how these individual receptor modes contribute to development are unknown. Here, we show that mice carrying targeted knockin mutations in the corepressor Silencing Mediator of Retinoid and Thyroid hormone receptor (SMRT) that specifically disable SMRT function in NR signaling (SMRTmRID), display defects in cranial neural crest cell-derived structures and posterior homeotic transformations of axial vertebrae. SMRTmRID embryos show enhanced transcription of RAR targets including Hox loci, resulting in respecification of vertebral identities. Up-regulated histone acetylation and decreased H3K27 methylation are evident in the Hox loci whose somitic expression boundaries are rostrally shifted. Furthermore, enhanced recruitment of super elongation complex is evident in rapidly induced non-Pol II-paused targets in SMRTmRID embryonic stem cells. These results demonstrate that SMRT-dependent repression of RAR is critical to establish and maintain the somitic Hox code and segmental identity during fetal development via epigenetic marking of target loci.


Assuntos
Regulação da Expressão Gênica , Genes Homeobox/genética , Correpressor 2 de Receptor Nuclear/fisiologia , Somitos/fisiologia , Transcrição Gênica , Tretinoína/farmacologia , Animais , Antineoplásicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Crista Neural/citologia , Crista Neural/fisiologia , Somitos/citologia , Somitos/efeitos dos fármacos
3.
Proc Natl Acad Sci U S A ; 110(47): 18820-5, 2013 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-24191050

RESUMO

Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-ß and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression.


Assuntos
Medula Óssea/metabolismo , Citocinas/metabolismo , Repressão Epigenética/fisiologia , Correpressor 2 de Receptor Nuclear/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Transdução de Sinais/fisiologia , Trombopoetina/genética , Fosfatase Alcalina/sangue , Animais , Benzotiazóis , Cálcio/sangue , Proliferação de Células/efeitos dos fármacos , Primers do DNA/genética , Diaminas , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Técnicas de Introdução de Genes , Luciferases , Megacariócitos/metabolismo , Camundongos , Correpressor 2 de Receptor Nuclear/genética , Compostos Orgânicos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Reação em Cadeia da Polimerase , Mielofibrose Primária/etiologia , Quinolinas , Trombopoetina/biossíntese , Fator de Crescimento Transformador beta/metabolismo
4.
Diabetologia ; 57(5): 860-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24619218

RESUMO

The ability to adapt to cycles of feast and famine is critical for survival. Communication between multiple metabolic organs must be integrated to properly metabolise nutrients. By controlling networks of genes in major metabolic organs, nuclear hormone receptors (NHRs) play central roles in regulating metabolism in a tissue-specific manner. NHRs also establish daily rhythmicity by controlling the expression of core clock genes both centrally and peripherally. Recent findings show that many of the metabolic effects of NHRs are mediated through certain members of the fibroblast growth factor (FGF) family. This review focuses on the roles of NHRs in critical metabolic organs, including adipose tissue, liver and muscle, during the fed and fasted states, as well as their roles in circadian metabolism and downstream regulation of FGFs.


Assuntos
Receptores Citoplasmáticos e Nucleares/fisiologia , Tecido Adiposo/metabolismo , Animais , Ritmo Circadiano , Jejum , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/metabolismo , Homeostase , Humanos , Ligantes , Fígado/metabolismo , Modelos Biológicos , Músculos/metabolismo , Tiazolidinedionas/química
5.
Proc Natl Acad Sci U S A ; 108(8): 3412-7, 2011 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-21300871

RESUMO

The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)(mRID1) in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRT(mRID1) mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRT(mRID1) mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRT(mRID1) mice are both insulin-insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases.


Assuntos
Tecido Adiposo/metabolismo , Dieta/efeitos adversos , Resistência à Insulina , Correpressor 2 de Receptor Nuclear/fisiologia , Obesidade/etiologia , Fosforilação Oxidativa , Animais , Homeostase , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos
6.
Proc Natl Acad Sci U S A ; 106(52): 22504-9, 2009 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-20018750

RESUMO

Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as thiazolidinediones (TZDs) are widely used to treat type 2 diabetes, how its activation in individual tissues contributes to TZD's therapeutic action remains controversial. As TZDs are known to have receptor-independent effects, we sought to establish gain-of-function animal models to delineate the receptor's insulin-sensitizing actions. Unexpectedly, we find that selective activation of PPARgamma in adipocytes, but not in macrophages, is sufficient for whole-body insulin sensitization equivalent to systemic TZD treatment. In addition to improved adipokine, inflammatory, and lipid profiles, PPARgamma activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARgamma-activated adipocytes broadly suppress induction of inflammatory cytokines and C-X-C family chemokines in macrophages. Collectively, these data describe an "adipocentric" model in which adipose activation of PPARgamma is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARgamma modulators in diabetic therapy.


Assuntos
Adipócitos Brancos/metabolismo , Insulina/metabolismo , PPAR gama/metabolismo , Células 3T3-L1 , Adipócitos Brancos/efeitos dos fármacos , Animais , Linhagem Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Expressão Gênica , Humanos , Hipoglicemiantes/farmacologia , Mediadores da Inflamação/metabolismo , Insulina/sangue , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , PPAR gama/agonistas , PPAR gama/genética , Pioglitazona , Ratos , Ratos Zucker , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Tiazolidinedionas/farmacologia
7.
Proc Natl Acad Sci U S A ; 105(50): 20021-6, 2008 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-19066220

RESUMO

The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of SMRT (SMRT(mRID)) that solely disrupts its interaction with nuclear hormone receptors (NHRs). SMRT(mRID) mice are viable and exhibit no gross developmental abnormalities, demonstrating that the reported lethality of SMRT knockouts is determined by non-NHR transcription factors. However, SMRT(mRID) mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRT(mRID)-derived MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. Collectively, our results demonstrate that SMRT-RID-dependent repression is a key determinant of the adipogenic set point as well as an integrator of glucose metabolism and whole-body metabolic homeostasis.


Assuntos
Adipogenia/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Repressoras/metabolismo , Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/genética , Animais , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Genes Letais , Glucose/metabolismo , Homeostase/genética , Camundongos , Camundongos Mutantes , Correpressor 2 de Receptor Nuclear , PPAR gama/metabolismo , Estrutura Terciária de Proteína , Proteínas Repressoras/genética , Hormônios Tireóideos/metabolismo
8.
Sci Rep ; 5: 13378, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26293987

RESUMO

In this paper we have used second harmonic generation (SHG) and phasor approach to auto fluorescence lifetime imaging (FLIM) to obtain fingerprints of different collagens and then used these fingerprints to observe bone marrow fibrosis in the mouse femur. This is a label free approach towards fast automatable detection of fibrosis in tissue samples. FLIM has previously been used as a method of contrast in different tissues and in this paper phasor approach to FLIM is used to separate collagen I from collagen III, the markers of fibrosis, the largest groups of disorders that are often without any effective therapy. Often characterized by an increase in collagen content of the corresponding tissue, the samples are usually visualized by histochemical staining, which is pathologist dependent and cannot be automated.


Assuntos
Colágeno/isolamento & purificação , Fibrose/diagnóstico , Imagem Óptica/métodos , Animais , Galinhas , Fêmur/patologia , Géis , Humanos , Camundongos , Ratos , Processamento de Sinais Assistido por Computador
9.
J Korean Med Sci ; 19(4): 631-3, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15308863

RESUMO

Although ophthalmoplegia following snake bites is not indicative of a serious neurotoxic complication, symptoms of diplopia, dizziness and ocular discomfort can be emotionally devastating for patients. The authors experienced two cases of ophthalmoplegia following snake bites in Korea. The patients complained of diplopia that had developed several hours after the snake bites. The diplopia did not improve with antivenom treatment, but resolved completely after several injections of neostigmine.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Oftalmoplegia/tratamento farmacológico , Oftalmoplegia/etiologia , Mordeduras de Serpentes/complicações , Adolescente , Animais , Criança , Diplopia/tratamento farmacológico , Diplopia/etiologia , Feminino , Humanos , Masculino , Neostigmina/uso terapêutico
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