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[PMID]: 29240764 [Au] Autor: Harbison ST; Serrano Negron YL; Hansen NF; Lobell AS [Ad] Endereço: Laboratory of Systems Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States of America. [Ti] Título: Selection for long and short sleep duration in Drosophila melanogaster reveals the complex genetic network underlying natural variation in sleep. [So] Source: PLoS Genet;13(12):e1007098, 2017 Dec. [Is] ISSN: 1553-7404 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Why do some individuals need more sleep than others? Forward mutagenesis screens in flies using engineered mutations have established a clear genetic component to sleep duration, revealing mutants that convey very long or short sleep. Whether such extreme long or short sleep could exist in natural populations was unknown. We applied artificial selection for high and low night sleep duration to an outbred population of Drosophila melanogaster for 13 generations. At the end of the selection procedure, night sleep duration diverged by 9.97 hours in the long and short sleeper populations, and 24-hour sleep was reduced to 3.3 hours in the short sleepers. Neither long nor short sleeper lifespan differed appreciably from controls, suggesting little physiological consequences to being an extreme long or short sleeper. Whole genome sequence data from seven generations of selection revealed several hundred thousand changes in allele frequencies at polymorphic loci across the genome. Combining the data from long and short sleeper populations across generations in a logistic regression implicated 126 polymorphisms in 80 candidate genes, and we confirmed three of these genes and a larger genomic region with mutant and chromosomal deficiency tests, respectively. Many of these genes could be connected in a single network based on previously known physical and genetic interactions. Candidate genes have known roles in several classic, highly conserved developmental and signaling pathways-EGFR, Wnt, Hippo, and MAPK. The involvement of highly pleiotropic pathway genes suggests that sleep duration in natural populations can be influenced by a wide variety of biological processes, which may be why the purpose of sleep has been so elusive. [Mh] Termos MeSH primário: Drosophila melanogaster/genética Redes Reguladoras de Genes/genética Seleção Genética Transdução de Sinais/genética Sono/genética [Mh] Termos MeSH secundário: Animais Proteínas de Drosophila/genética Proteínas de Drosophila/metabolismo Drosophila melanogaster/metabolismo Feminino Frequência do Gene Peptídeos e Proteínas de Sinalização Intracelular/metabolismo Masculino Proteínas Quinases Ativadas por Mitógeno/metabolismo Mutagênese Mutação Fenótipo Polimorfismo Genético Proteínas Serina-Treonina Quinases/metabolismo Receptor do Fator de Crescimento Epidérmico/genética Receptor do Fator de Crescimento Epidérmico/metabolismo Receptores de Peptídeos de Invertebrados/genética Receptores de Peptídeos de Invertebrados/metabolismo Fatores de Tempo Sequenciamento Completo do Genoma Proteína Wnt1/genética Proteína Wnt1/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Drosophila Proteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (Receptors, Invertebrate Peptide); 0 (Wnt1 Protein); 0 (wg protein, Drosophila); EC 2.7.10.1 (Egfr protein, Drosophila); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (hpo protein, Drosophila); EC 2.7.11.24 (Mitogen-Activated Protein Kinases) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171229 [Lr] Data última revisão: 171229 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171215 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pgen.1007098

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[PMID]: 29065163 [Au] Autor: Gao H; He F; Lin X; Wu Y [Ad] Endereço: School of Life Sciences, University of Science and Technology of China, Hefei, China. [Ti] Título: Drosophila VAMP7 regulates Wingless intracellular trafficking. [So] Source: PLoS One;12(10):e0186938, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Drosophila Wingless (Wg) is a morphogen that determines cell fate during development. Previous studies have shown that endocytic pathways regulate Wg trafficking and signaling. Here, we showed that loss of vamp7, a gene required for vesicle fusion, dramatically increased Wg levels and decreased Wg signaling. Interestingly, we found that levels of Dally-like (Dlp), a glypican that can interact with Wg to suppress Wg signaling at the dorsoventral boundary of the Drosophila wing, were also increased in vamp7 mutant cells. Moreover, Wg puncta in Rab4-dependent recycling endosomes were Dlp positive. We hypothesize that VAMP7 is required for Wg intracellular trafficking and the accumulation of Wg in Rab4-dependent recycling endosomes might affect Wg signaling. [Mh] Termos MeSH primário: Proteínas de Drosophila/metabolismo Proteínas de Drosophila/fisiologia Drosophila/genética Proteínas R-SNARE/fisiologia Proteína Wnt1/metabolismo [Mh] Termos MeSH secundário: Animais Transporte Biológico Proteínas de Drosophila/genética Proteínas R-SNARE/genética Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Drosophila Proteins); 0 (R-SNARE Proteins); 0 (VAMP7 protein, Drosophila); 0 (Wnt1 Protein); 0 (wg protein, Drosophila) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171113 [Lr] Data última revisão: 171113 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171025 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0186938

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[PMID]: 29028797 [Au] Autor: Verghese S; Su TT [Ad] Endereço: Department of Molecular, Cellular and Developmental Biology, UCB, University of Colorado, Boulder, CO, United States of America. [Ti] Título: STAT, Wingless, and Nurf-38 determine the accuracy of regeneration after radiation damage in Drosophila. [So] Source: PLoS Genet;13(10):e1007055, 2017 Oct. [Is] ISSN: 1553-7404 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We report here a study of regeneration in Drosophila larval wing imaginal discs after damage by ionizing radiation. We detected faithful regeneration that restored a wing disc and abnormal regeneration that produced an extra wing disc. We describe a sequence of changes in cell number, location and fate that occur to produce an ectopic disc. We identified a group of cells that not only participate in ectopic disc formation but also recruit others to do so. STAT92E (Drosophila STAT3/5) and Nurf-38, which encodes a member of the Nucleosome Remodeling Factor complex, oppose each other in these cells to modulate the frequency of ectopic disc growth. The picture that emerges is one in which activities like STAT increase after radiation damage and fulfill essential roles in rebuilding the tissue. But such activities must be kept in check so that one and only one wing disc is regenerated. [Mh] Termos MeSH primário: Proteínas de Drosophila/genética Pirofosfatases/genética Regeneração/genética Fatores de Transcrição STAT/genética Proteína Wnt1/genética [Mh] Termos MeSH secundário: Animais Apoptose/efeitos da radiação Drosophila melanogaster/genética Drosophila melanogaster/crescimento & desenvolvimento Drosophila melanogaster/efeitos da radiação Regulação da Expressão Gênica no Desenvolvimento/efeitos da radiação Discos Imaginais/crescimento & desenvolvimento Discos Imaginais/lesões Discos Imaginais/efeitos da radiação Larva/genética Larva/crescimento & desenvolvimento Larva/efeitos da radiação Regeneração/efeitos da radiação Asas de Animais/crescimento & desenvolvimento Asas de Animais/efeitos da radiação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Drosophila Proteins); 0 (STAT Transcription Factors); 0 (Wnt1 Protein); 0 (wg protein, Drosophila); EC 3.6.1.- (Pyrophosphatases); EC 3.6.1.1 (Nurf-38 protein, Drosophila) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171111 [Lr] Data última revisão: 171111 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171014 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pgen.1007055

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[PMID]: 28893947 [Au] Autor: Jia S; Zhou J; Fanelli C; Wee Y; Bonds J; Schneider P; Mues G; D'Souza RN [Ad] Endereço: School of Dentistry, University of Utah, Salt Lake City, UT 84112, USA. [Ti] Título: Small-molecule Wnt agonists correct cleft palates in mutant mice . [So] Source: Development;144(20):3819-3828, 2017 10 15. [Is] ISSN: 1477-9129 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Clefts of the palate and/or lip are among the most common human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We show that the absence of Pax9 alters the expression of Wnt pathway genes including and , proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 are shown by the genetic rescue of secondary palate clefts in embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant mice restored Wnt signaling and led to the growth and fusion of palatal shelves, as marked by an increase in cell proliferation and osteogenesis , while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that this functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single-gene disorders. [Mh] Termos MeSH primário: Fissura Palatina/genética Fatores de Transcrição Box Pareados/genética Palato/embriologia Proteína Wnt1/agonistas Proteína Wnt1/genética [Mh] Termos MeSH secundário: Animais Padronização Corporal Proliferação Celular Feminino Perfilação da Expressão Gênica Regulação da Expressão Gênica no Desenvolvimento Peptídeos e Proteínas de Sinalização Intercelular/genética Masculino Camundongos Camundongos Transgênicos Morfogênese Osteogênese Fenótipo Ligação Proteica Via de Sinalização Wnt [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Dkk1 protein, mouse); 0 (Dkk2 protein, mouse); 0 (Intercellular Signaling Peptides and Proteins); 0 (Paired Box Transcription Factors); 0 (Pax9 protein, mouse); 0 (Wnt1 Protein); 0 (Wnt1 protein, mouse) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171126 [Lr] Data última revisão: 171126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170913 [St] Status: MEDLINE [do] DOI: 10.1242/dev.157750

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[PMID]: 28860114 [Au] Autor: Kopke DL; Lima SC; Alexandre C; Broadie K [Ad] Endereço: Department of Biological Sciences, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235, USA. [Ti] Título: Notum coordinates synapse development via extracellular regulation of Wingless trans-synaptic signaling. [So] Source: Development;144(19):3499-3510, 2017 10 01. [Is] ISSN: 1477-9129 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Synaptogenesis requires orchestrated communication between pre- and postsynaptic cells via coordinated trans-synaptic signaling across the extracellular synaptomatrix. The first Wnt signaling ligand discovered, Wingless (Wg; Wnt1 in mammals), plays crucial roles in synaptic development, regulating synapse architecture as well as functional differentiation. Here, we investigate synaptogenic functions of the secreted extracellular deacylase Notum, which restricts Wg signaling by cleaving an essential palmitoleate moiety. At the glutamatergic neuromuscular junction (NMJ) synapse, we find that Notum secreted from the postsynaptic muscle acts to strongly modulate synapse growth, structural architecture, ultrastructural development and functional differentiation. In null flies, we find upregulated extracellular Wg ligand and nuclear trans-synaptic signal transduction, as well as downstream misregulation of both pre- and postsynaptic molecular assembly. Structural, functional and molecular synaptogenic defects are all phenocopied by Wg overexpression, suggesting that Notum acts solely by inhibiting Wg trans-synaptic signaling. Moreover, these synaptic development phenotypes are suppressed by genetically correcting Wg levels in null mutants, indicating that Notum normally functions to coordinate synaptic structural and functional differentiation via negative regulation of Wg trans-synaptic signaling in the extracellular synaptomatrix. [Mh] Termos MeSH primário: Proteínas de Drosophila/metabolismo Drosophila melanogaster/metabolismo Espaço Extracelular/metabolismo Transdução de Sinais Sinapses/metabolismo Proteína Wnt1/metabolismo [Mh] Termos MeSH secundário: Animais Diferenciação Celular Movimento Celular Vesículas Citoplasmáticas/metabolismo Vesículas Citoplasmáticas/ultraestrutura Drosophila melanogaster/ultraestrutura Ligantes Músculos/metabolismo Mutação/genética Neuroglia/metabolismo Junção Neuromuscular/metabolismo Fenótipo Sinapses/ultraestrutura [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Drosophila Proteins); 0 (Ligands); 0 (Notum protein, Drosophila); 0 (Wnt1 Protein); 0 (wg protein, Drosophila) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171126 [Lr] Data última revisão: 171126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170902 [St] Status: MEDLINE [do] DOI: 10.1242/dev.148130

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[PMID]: 28751573 [Au] Autor: Wang D; Wu F; Yuan H; Wang A; Kang GJ; Truong T; Chen L; McCallion AS; Gong X; Li S [Ad] Endereço: From the Department of Bioengineering (D.W., F.W., A.W., S.L.) and School of Optometry and Vision Science Graduate Program (D.W., G.J.K., T.T., L.C., X.G.), University of California, Berkeley; Department of Bioengineering (D.W., H.Y., S.L.) and Department of Medicine (S.L.), University of California [Ti] Título: Sox10 Cells Contribute to Vascular Development in Multiple Organs-Brief Report. [So] Source: Arterioscler Thromb Vasc Biol;37(9):1727-1731, 2017 Sep. [Is] ISSN: 1524-4636 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE: Previous genetic lineage tracing studies showed that Sox10 cells differentiate into vascular mural cells, limited to neural crest-derived blood vessels in craniofacial tissues, aortic arch, pulmonary arch arteries, brachiocephalic, carotid arteries, and thymus. The purpose of this study was to investigate the contribution of Sox10 cells to the vascular development in other tissues and organs and their relationship with neural crest. APPROACH AND RESULTS: Using genetic lineage tracing technique based on Cre/LoxP system, we examined blood vessels in the adult organs of the mice expressing Sox10-Cre/Rosa-LoxP-red fluorescent protein or Wnt1-Cre/Rosa-LoxP-red fluorescent protein by immunohistological analysis. In addition to previously reported tissues and organs derived from neural crest, we showed that Sox10 cells also contributed to vascular mural cells in the lung, spleen, and kidney, which are derived from non-neural crest origin as evidenced by red fluorescent protein-negative blood vessels in these 3 organs of Wnt1-Cre/Rosa-LoxP-red fluorescent protein mice. CONCLUSIONS: This study demonstrates that Sox10 cells contribute to pericytes and smooth muscle cells in most parts of the body, including those from neural crest and non-neural crest, which has significant implications in vascular remodeling under physiological and pathological conditions. [Mh] Termos MeSH primário: Linhagem da Célula Rim/irrigação sanguínea Pulmão/irrigação sanguínea Músculo Liso Vascular/metabolismo Miócitos de Músculo Liso/metabolismo Crista Neural/metabolismo Pericitos/metabolismo Fatores de Transcrição SOXE/metabolismo Baço/irrigação sanguínea [Mh] Termos MeSH secundário: Animais Imunofluorescência Genótipo Integrases/genética Proteínas Luminescentes/biossíntese Proteínas Luminescentes/genética Camundongos Transgênicos Morfogênese Músculo Liso Vascular/citologia Neovascularização Fisiológica Crista Neural/citologia Fenótipo Fatores de Transcrição SOXE/genética Remodelação Vascular Proteína Wnt1/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Luminescent Proteins); 0 (SOXE Transcription Factors); 0 (Sox10 protein, mouse); 0 (Wnt1 Protein); 0 (Wnt1 protein, mouse); 0 (red fluorescent protein); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170906 [Lr] Data última revisão: 170906 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170729 [St] Status: MEDLINE [do] DOI: 10.1161/ATVBAHA.117.309774

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[PMID]: 28663257 [Au] Autor: Sawada H; Rateri DL; Moorleghen JJ; Majesky MW; Daugherty A [Ad] Endereço: From the Saha Cardiovascular Research Center (H.S., D.L.R., J.J.M., A.D.) and Department of Physiology (A.D.), University of Kentucky, Lexington; Seattle Children's Research Institute, Washington (M.W.M.); and Department of Pediatrics and Department of Pathology, University of Washington, Seattle (M [Ti] Título: Smooth Muscle Cells Derived From Second Heart Field and Cardiac Neural Crest Reside in Spatially Distinct Domains in the Media of the Ascending Aorta-Brief Report. [So] Source: Arterioscler Thromb Vasc Biol;37(9):1722-1726, 2017 Sep. [Is] ISSN: 1524-4636 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE: Smooth muscle cells (SMCs) of the proximal thoracic aorta are embryonically derived from the second heart field (SHF) and cardiac neural crest (CNC). However, distributions of these embryonic origins are not fully defined. The regional distribution of SMCs of different origins is speculated to cause region-specific aortopathies. Therefore, the aim of this study was to determine the distribution of SMCs of SHF and CNC origins in the proximal thoracic aorta. APPROACH AND RESULTS: Mice with repressed LacZ in the ROSA26 locus were bred to those expressing controlled by either the Wnt1 or Mef2c (myocyte-specific enhancer factor 2c) promoter to trace CNC- and SHF-derived SMCs, respectively. Thoracic aortas were harvested, and activity of ß-galactosidase was determined. Aortas from Wnt1- mice had ß-galactosidase-positive areas throughout the region from the proximal ascending aorta to just distal of the subclavian arterial branch. Unexpectedly, ß-galactosidase-positive areas in Mef2c- mice extended from the aortic root throughout the ascending aorta. This distribution occurred independent of sex and aging. Cross and sagittal aortic sections demonstrated that CNC-derived cells populated the inner medial aspect of the anterior region of the ascending aorta and transmurally in the media of the posterior region. Interestingly, outer medial cells throughout anterior and posterior ascending aortas were derived from the SHF. ß-Galactosidase-positive medial cells of both origins colocalized with an SMC marker, α-actin. CONCLUSIONS: Both CNC- and SHF-derived SMCs populate the media throughout the ascending aorta. The outer medial cells of the ascending aorta form a sleeve populated by SHF-derived SMCs. [Mh] Termos MeSH primário: Linhagem da Célula Coração/embriologia Músculo Liso Vascular/fisiologia Miocárdio Miócitos de Músculo Liso/fisiologia Crista Neural/fisiologia Túnica Média/fisiologia [Mh] Termos MeSH secundário: Fatores Etários Animais Aorta Torácica/embriologia Aorta Torácica/metabolismo Aorta Torácica/fisiologia Feminino Regulação da Expressão Gênica no Desenvolvimento Genótipo Integrases/genética Óperon Lac Fatores de Transcrição MEF2/genética Masculino Camundongos Transgênicos Morfogênese Músculo Liso Vascular/embriologia Músculo Liso Vascular/metabolismo Miocárdio/metabolismo Miócitos de Músculo Liso/metabolismo Crista Neural/embriologia Crista Neural/metabolismo Fenótipo Regiões Promotoras Genéticas RNA não Traduzido/genética Fatores Sexuais Túnica Média/embriologia Túnica Média/metabolismo Proteína Wnt1/genética beta-Galactosidase/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Gt(ROSA)26Sor non-coding RNA, mouse); 0 (MEF2 Transcription Factors); 0 (Mef2c protein, mouse); 0 (RNA, Untranslated); 0 (Wnt1 Protein); 0 (Wnt1 protein, mouse); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases); EC 3.2.1.23 (beta-Galactosidase) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170906 [Lr] Data última revisão: 170906 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170701 [St] Status: MEDLINE [do] DOI: 10.1161/ATVBAHA.117.309599

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[PMID]: 28628035 [Au] Autor: Rauch F [Ti] Título: The brains of the bones: how osteocytes use WNT1 to control bone formation. [So] Source: J Clin Invest;127(7):2539-2540, 2017 Jun 30. [Is] ISSN: 1558-8238 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: WNT proteins drive the development and maintenance of many tissues, including bone. It is less clear which of the many WNT proteins act on bone or where these WNTs act in the skeleton; however, loss-of-function mutations in WNT1 cause bone fragility in children and adults. In this issue of the JCI, Joeng and colleagues demonstrate that bone formation is under the control of WNT1 produced by osteocytes, the cells that reside deep in the bone matrix and form dendritic networks. The implication of WNT1 in the control of bone formation identifies a potential new target for the treatment of low bone mass disorders, such as osteoporosis. [Mh] Termos MeSH primário: Osteócitos/metabolismo Osteogênese Osteoporose/metabolismo Proteína Wnt1/metabolismo [Mh] Termos MeSH secundário: Adolescente Adulto Criança Pré-Escolar Feminino Seres Humanos Lactente Masculino Osteócitos/patologia Osteoporose/genética Osteoporose/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (WNT1 protein, human); 0 (Wnt1 Protein) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170914 [Lr] Data última revisão: 170914 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170620 [St] Status: MEDLINE

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[PMID]: 28628032 [Au] Autor: Joeng KS; Lee YC; Lim J; Chen Y; Jiang MM; Munivez E; Ambrose C; Lee BH [Ad] Endereço: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [Ti] Título: Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. [So] Source: J Clin Invest;127(7):2678-2688, 2017 Jun 30. [Is] ISSN: 1558-8238 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Mutations in WNT1 cause osteogenesis imperfecta (OI) and early-onset osteoporosis, identifying it as a key Wnt ligand in human bone homeostasis. However, how and where WNT1 acts in bone are unclear. To address this mechanism, we generated late-osteoblast-specific and osteocyte-specific WNT1 loss- and gain-of-function mouse models. Deletion of Wnt1 in osteocytes resulted in low bone mass with spontaneous fractures similar to that observed in OI patients. Conversely, Wnt1 overexpression from osteocytes stimulated bone formation by increasing osteoblast number and activity, which was due in part to activation of mTORC1 signaling. While antiresorptive therapy is the mainstay of OI treatment, it has limited efficacy in WNT1-related OI. In this study, anti-sclerostin antibody (Scl-Ab) treatment effectively improved bone mass and dramatically decreased fracture rate in swaying mice, a model of global Wnt1 loss. Collectively, our data suggest that WNT1-related OI and osteoporosis are caused in part by decreased mTORC1-dependent osteoblast function resulting from loss of WNT1 signaling in osteocytes. As such, this work identifies an anabolic function of osteocytes as a source of Wnt in bone development and homoeostasis, complementing their known function as targets of Wnt signaling in regulating osteoclastogenesis. Finally, this study suggests that Scl-Ab is an effective genotype-specific treatment option for WNT1-related OI and osteoporosis. [Mh] Termos MeSH primário: Fraturas Ósseas/metabolismo Homeostase Osteócitos/metabolismo Osteogênese Imperfeita/metabolismo Osteoporose/metabolismo Via de Sinalização Wnt Proteína Wnt1/metabolismo [Mh] Termos MeSH secundário: Animais Anticorpos/farmacologia Fraturas Ósseas/tratamento farmacológico Fraturas Ósseas/genética Fraturas Ósseas/patologia Glicoproteínas/antagonistas & inibidores Glicoproteínas/genética Glicoproteínas/metabolismo Seres Humanos Alvo Mecanístico do Complexo 1 de Rapamicina Camundongos Camundongos Transgênicos Complexos Multiproteicos/genética Complexos Multiproteicos/metabolismo Osteócitos/patologia Osteogênese Imperfeita/tratamento farmacológico Osteogênese Imperfeita/genética Osteogênese Imperfeita/patologia Osteoporose/tratamento farmacológico Osteoporose/genética Osteoporose/patologia Serina-Treonina Quinases TOR/genética Serina-Treonina Quinases TOR/metabolismo Proteína Wnt1/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies); 0 (Glycoproteins); 0 (Multiprotein Complexes); 0 (Sost protein, mouse); 0 (Wnt1 Protein); 0 (Wnt1 protein, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170620 [St] Status: MEDLINE

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[PMID]: 28576832 [Au] Autor: Cao J; Singh SP; McClung JA; Joseph G; Vanella L; Barbagallo I; Jiang H; Falck JR; Arad M; Shapiro JI; Abraham NG [Ad] Endereço: Departments of Medicine and Pharmacology, New York Medical College, Valhalla, New York. [Ti] Título: EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice. [So] Source: Am J Physiol Heart Circ Physiol;313(2):H368-H380, 2017 Aug 01. [Is] ISSN: 1522-1539 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1α, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a "browning" pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome. The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.Listen to this article's corresponding podcast at http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017. [Mh] Termos MeSH primário: Tecido Adiposo/efeitos dos fármacos Cardiomiopatias/prevenção & controle Eicosanoides/farmacologia Heme Oxigenase-1/metabolismo Proteínas de Membrana/metabolismo Miócitos Cardíacos/efeitos dos fármacos Proteína Sobre-Expressa em Nefroblastoma/metabolismo Obesidade/tratamento farmacológico Via de Sinalização Wnt/efeitos dos fármacos Proteína Wnt1/metabolismo [Mh] Termos MeSH secundário: Células 3T3-L1 Adipocinas/metabolismo Tecido Adiposo/enzimologia Tecido Adiposo/fisiopatologia Animais Biomarcadores/sangue Glicemia/efeitos dos fármacos Glicemia/metabolismo Pressão Sanguínea Cardiomiopatias/enzimologia Cardiomiopatias/etiologia Cardiomiopatias/fisiopatologia Modelos Animais de Doenças Mediadores da Inflamação/metabolismo Camundongos Camundongos Knockout Mitocôndrias Cardíacas/efeitos dos fármacos Mitocôndrias Cardíacas/enzimologia Miócitos Cardíacos/enzimologia Obesidade/complicações Obesidade/enzimologia Obesidade/fisiopatologia Consumo de Oxigênio Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/deficiência Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética Remodelação Ventricular Ganho de Peso/efeitos dos fármacos Proteínas Wnt/metabolismo beta Catenina [Pt] Tipo de publicação: JOURNAL ARTICLE; WEBCASTS [Nm] Nome de substância: 0 (Adipokines); 0 (Biomarkers); 0 (Blood Glucose); 0 (CTNNB1 protein, mouse); 0 (Eicosanoids); 0 (Inflammation Mediators); 0 (Membrane Proteins); 0 (Nephroblastoma Overexpressed Protein); 0 (Nov protein, mouse); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Ppargc1a protein, mouse); 0 (Wnt Proteins); 0 (Wnt1 Protein); 0 (Wnt1 protein, mouse); 0 (Wnt5b protein, mouse); 0 (beta Catenin); EC 1.14.14.18 (Heme Oxygenase-1); EC 1.14.14.18 (Hmox1 protein, mouse) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170907 [Lr] Data última revisão: 170907 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170604 [St] Status: MEDLINE [do] DOI: 10.1152/ajpheart.00093.2017

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