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1.
Nat Commun ; 12(1): 5127, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493721

RESUMO

Intricate color patterns are a defining aspect of morphological diversity in the Felidae. We applied morphological and single-cell gene expression analysis to fetal skin of domestic cats to identify when, where, and how, during fetal development, felid color patterns are established. Early in development, we identify stripe-like alterations in epidermal thickness preceded by a gene expression pre-pattern. The secreted Wnt inhibitor encoded by Dickkopf 4 plays a central role in this process, and is mutated in cats with the Ticked pattern type. Our results bring molecular understanding to how the leopard got its spots, suggest that similar mechanisms underlie periodic color pattern and periodic hair follicle spacing, and identify targets for diverse pattern variation in other mammals.


Assuntos
Gatos/genética , Regulação da Expressão Gênica no Desenvolvimento , Pigmentação/genética , Animais , Animais Domésticos , Gatos/crescimento & desenvolvimento , Epiderme/crescimento & desenvolvimento , Epiderme/metabolismo , Genótipo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Queratinócitos/metabolismo , Mutação , Fenótipo , Análise de Célula Única , Pele/anatomia & histologia , Pele/crescimento & desenvolvimento , Pele/metabolismo , Via de Sinalização Wnt
2.
Elife ; 52016 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-26880558

RESUMO

Live-cell imaging and genetic tools reveal a new way in which pigment cells communicate in zebrafish.


Assuntos
Melanóforos , Peixe-Zebra/genética , Animais , Evolução Biológica , Fenótipo , Pigmentação/genética , Proteínas de Peixe-Zebra/genética
3.
Science ; 337(6101): 1536-41, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22997338

RESUMO

Color markings among felid species display both a remarkable diversity and a common underlying periodicity. A similar range of patterns in domestic cats suggests a conserved mechanism whose appearance can be altered by selection. We identified the gene responsible for tabby pattern variation in domestic cats as Transmembrane aminopeptidase Q (Taqpep), which encodes a membrane-bound metalloprotease. Analyzing 31 other felid species, we identified Taqpep as the cause of the rare king cheetah phenotype, in which spots coalesce into blotches and stripes. Histologic, genomic expression, and transgenic mouse studies indicate that paracrine expression of Endothelin3 (Edn3) coordinates localized color differences. We propose a two-stage model in which Taqpep helps to establish a periodic pre-pattern during skin development that is later implemented by differential expression of Edn3.


Assuntos
Aminopeptidases/genética , Gatos/genética , Endotelina-3/genética , Felidae/genética , Cor de Cabelo/genética , Metaloproteases/genética , Pele/metabolismo , Acinonyx/genética , Acinonyx/metabolismo , Alelos , Aminopeptidases/química , Aminopeptidases/metabolismo , Animais , Gatos/embriologia , Gatos/crescimento & desenvolvimento , Gatos/metabolismo , Endotelina-3/metabolismo , Epistasia Genética , Felidae/crescimento & desenvolvimento , Felidae/metabolismo , Regulação da Expressão Gênica , Frequência do Gene , Variação Genética , Cabelo/embriologia , Cabelo/crescimento & desenvolvimento , Folículo Piloso/embriologia , Haplótipos , Metaloproteases/química , Metaloproteases/metabolismo , Camundongos , Camundongos Transgênicos , Panthera/genética , Panthera/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Pele/anatomia & histologia , Pele/embriologia , Especificidade da Espécie
4.
Blood ; 118(13): 3622-33, 2011 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-21788341

RESUMO

Reduced gene dosage of ribosomal protein subunits has been implicated in 5q- myelodysplastic syndrome and Diamond Blackfan anemia, but the cellular and pathophysiologic defects associated with these conditions are enigmatic. Using conditional inactivation of the ribosomal protein S6 gene in laboratory mice, we found that reduced ribosomal protein gene dosage recapitulates cardinal features of the 5q- syndrome, including macrocytic anemia, erythroid hypoplasia, and megakaryocytic dysplasia with thrombocytosis, and that p53 plays a critical role in manifestation of these phenotypes. The blood cell abnormalities are accompanied by a reduction in the number of HSCs, a specific defect in late erythrocyte development, and suggest a disease-specific ontogenetic pathway for megakaryocyte development. Further studies of highly purified HSCs from healthy patients and from those with myelodysplastic syndrome link reduced expression of ribosomal protein genes to decreased RBC maturation and suggest an underlying and common pathophysiologic pathway for additional subtypes of myelodysplastic syndrome.


Assuntos
Dosagem de Genes , Síndromes Mielodisplásicas/genética , Proteínas Ribossômicas/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Regulação para Baixo/genética , Feminino , Dosagem de Genes/genética , Dosagem de Genes/fisiologia , Predisposição Genética para Doença , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/metabolismo , Proteínas Ribossômicas/metabolismo , Fatores de Risco , Proteína Supressora de Tumor p53/fisiologia
5.
Semin Hematol ; 48(2): 106-16, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21435507

RESUMO

Diamond Blackfan anemia (DBA) is a genetic syndrome characterized by red blood cell aplasia in association with developmental abnormalities such as growth retardation, orofacial, hand or limb malformations, urogenital anomalies, and heart defects. The only known cause is heterozygosity for mutations in genes encoding ribosomal proteins. Understanding how defective ribosome biogenesis and function, important for all cells, causes defects in erythropoiesis and tissue-specific phenotypes during development is paramount to the evolution of effective treatment protocols. Here, we discuss how animal models based on mammals, insects, and fish replicate genetic or developmental aspects of DBA and have led to the identification of pathways and candidate molecules that are important in the pathogenesis of the disease. A recurring theme in many of these models suggests that defective ribosome biogenesis induces a p53-dependent cell cycle checkpoint in cells that require high levels of ribosome production and leads to cell type-specific, whole animal phenotypes.


Assuntos
Anemia de Diamond-Blackfan/genética , Modelos Animais de Doenças , Proteína Supressora de Tumor p53/genética , Anemia de Diamond-Blackfan/metabolismo , Anemia de Diamond-Blackfan/patologia , Animais , Ciclo Celular/genética , Proteína Supressora de Tumor p53/metabolismo
6.
Nat Genet ; 40(8): 963-70, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18641651

RESUMO

Mutations in genes encoding ribosomal proteins cause the Minute phenotype in Drosophila and mice, and Diamond-Blackfan syndrome in humans. Here we report two mouse dark skin (Dsk) loci caused by mutations in Rps19 (ribosomal protein S19) and Rps20 (ribosomal protein S20). We identify a common pathophysiologic program in which p53 stabilization stimulates Kit ligand expression, and, consequently, epidermal melanocytosis via a paracrine mechanism. Accumulation of p53 also causes reduced body size and erythrocyte count. These results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.


Assuntos
Proteínas Ribossômicas/genética , Pigmentação da Pele , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Epidérmicas , Epiderme/metabolismo , Eritrócitos/metabolismo , Humanos , Queratinócitos/metabolismo , Melanócitos/metabolismo , Camundongos , Mutação , Proteína S6 Ribossômica/genética , Proteína S6 Ribossômica/metabolismo , Proteínas Ribossômicas/metabolismo , Fator de Células-Tronco/metabolismo
7.
J Invest Dermatol ; 127(1): 60-4, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16858417

RESUMO

With the goal of increasing the number of genetic entry points for studying physiologic processes and human disease, large-scale, systematic, chemical mutagenesis projects in mice have been initiated in several different centers. We have been studying mouse mutants that exhibit dominantly inherited defects in either skin and/or hair color. Here, we describe a bright coat color mutant, Bright coat color 1 (Bcc1), which develops light-colored hair at 4 weeks of age, and when homozygous exhibits oral leukoplakia and blistering, and growth retardation. We identified a missense mutation in mutant animals that predicts an N154S amino-acid substitution in the 1A domain of Keratin 4 (encoded by the Krt2-4 gene), a region known to be mutated in human patients with white sponge nevus (WSN). Bcc1 recapitulates the gross pathologic, histologic, and genetic aspects of the human disorder, WSN.


Assuntos
Modelos Animais de Doenças , Hamartoma/genética , Queratina-4/genética , Leucoplasia Oral/genética , Doenças da Boca/genética , Mutação de Sentido Incorreto , Animais , Cor de Cabelo/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mucosa Bucal/patologia
8.
J Invest Dermatol ; 126(5): 1013-6, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16528356

RESUMO

Chemical mutagenesis in the mouse has increased the utility of phenotype-driven genetics as a means for studying different organ systems, developmental pathways, and pathologic processes. From a large-scale screen for dominant phenotypes in mice, a novel class of pigmentation mutants was identified by dark skin (Dsk). We describe a Dsk mutant, Dsk12, which models the human disease, epidermolytic hyperkeratosis (EHK). At 2 days of age, mutant animals exhibit intraepidermal blisters and erosions at sites of trauma, and by 2 weeks of age develop significant hyperkeratosis. We identified a missense mutation in mutant animals that predicts an S194P amino acid substitution in the 1A domain of Keratin 1, a known target for human mutations that cause EHK. Dsk12 recapitulates the gross pathologic, histologic, and genetic aspects of the human disorder, EHK.


Assuntos
Hiperceratose Epidermolítica/etiologia , Queratinas/genética , Mutação de Sentido Incorreto , Pigmentação da Pele , Animais , Modelos Animais de Doenças , Hiperceratose Epidermolítica/genética , Camundongos , Camundongos Endogâmicos C3H
9.
Genes Dev ; 17(2): 214-28, 2003 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-12533510

RESUMO

Chemical mutagenesis in the mouse is a powerful approach for phenotype-driven genetics, but questions remain about the efficiency with which new mutations ascertained by their phenotype can be localized and identified, and that knowledge applied to a specific biological problem. During a global screen for dominant phenotypes in about 30,000 animals, a novel class of pigmentation mutants were identified by dark skin (Dsk). We determined the genetic map location, homozygous phenotype, and histology of 10 new Dsk and 2 new dark coat (Dcc) mutations, and identified mutations in Agouti (Met1Leu, Dcc4), Sox18 (Leu220ter, Dcc1), Keratin 2e (Thr500Pro, Dsk2), and Egfr (Leu863Gln, Dsk5). Cutaneous effects of most Dsk mutations are limited to melanocytes, except for the Keratin 2e and Egfr mutations, in which hyperkeratosis and epidermal thickening precede epidermal melanocytosis by 3-6 wk. The Dsk2 mutation is likely to impair intermediate filament assembly, leading to cytolysis of suprabasal keratinocytes and secondary hyperkeratosis and melanocytosis. The Dsk5 mutation causes increased tyrosine kinase activity and a decrease in steady-state receptor levels in vivo. The Dsk mutations represent genes or map locations not implicated previously in pigmentation, and delineate a developmental pathway in which mutations can be classified on the basis of body region, microscopic site, and timing of pigment accumulation.


Assuntos
Pigmentação da Pele/genética , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Receptores ErbB/genética , Genes Dominantes , Homozigoto , Humanos , Queratinas/genética , Queratinas/metabolismo , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Fenótipo , Homologia de Sequência de Aminoácidos , Pele/embriologia , Pele/crescimento & desenvolvimento , Pele/metabolismo
10.
J Biol Chem ; 278(18): 15661-8, 2003 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-12473650

RESUMO

Laminin-5, a major adhesive ligand for epithelial cells, undergoes processing of its gamma2 and alpha3 chains. This study investigated the mechanism of laminin-5 processing by keratinocytes. BI-1 (BMP-1 isoenzyme inhibitor-1), a selective inhibitor of a small group of astacin-like metalloproteinases, which includes bone morphogenetic protein 1 (BMP-1), mammalian Tolloid (mTLD), mammalian Tolloid-like 1 (mTLL-1), and mammalian Tolloid-like 2 (mTLL-2), inhibited the processing of laminin-5 gamma2 and alpha3 chains in keratinocyte cultures in a dose-dependent manner. In a proteinase survey, all BMP-1 isoenzymes processed human laminin-5 gamma2 and alpha3 chains to 105- and 165-kDa fragments, respectively. In contrast, MT1-MMP and MMP-2 did not cleave the gamma2 chain of human laminin-5 but processed the rat laminin gamma2 chain to an 80-kDa fragment. An immunoblot and quantitative PCR survey of the BMP-1 isoenzymes revealed expression of mTLD in primary keratinocyte cultures but little or no expression of BMP-1, mTLL-1, or mTLL-2. mTLD was shown to cleave the gamma2 chain at the same site as the previously identified BMP-1 cleavage site. In addition, mTLD/BMP-1 null mice were shown to have deficient laminin-5 processing. Together, these data identify laminin-5 as a substrate for mTLD, suggesting a role for laminin-5 processing by mTLD in the skin.


Assuntos
Moléculas de Adesão Celular/metabolismo , Proteínas Fúngicas , Queratinócitos/metabolismo , Metaloproteinase 2 da Matriz/fisiologia , Metaloendopeptidases/fisiologia , Proteínas/fisiologia , Pele/metabolismo , Proteínas Morfogenéticas Ósseas , Moléculas de Adesão Celular/química , Células Cultivadas , Fibrinolisina/fisiologia , Humanos , Isoenzimas/fisiologia , Metaloproteinase 14 da Matriz , Metaloproteinases da Matriz Associadas à Membrana , Metaloproteases , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Metaloproteases Semelhantes a Toloide
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