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1.
Proc Natl Acad Sci U S A ; 120(1): e2209062120, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36577070

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) are a heterogeneous group of cells with expansion, differentiation, and repopulation capacities. How HSPCs orchestrate the stemness state with diverse lineage differentiation at steady condition or acute stress remains largely unknown. Here, we show that zebrafish mutants that are deficient in an epigenetic regulator Atf7ip or Setdb1 methyltransferase undergo excessive myeloid differentiation with impaired HSPC expansion, manifesting a decline in T cells and erythroid lineage. We find that Atf7ip regulates hematopoiesis through Setdb1-mediated H3K9me3 modification and chromatin remodeling. During hematopoiesis, the interaction of Atf7ip and Setdb1 triggers H3K9me3 depositions in hematopoietic regulatory genes including cebpß and cdkn1a, preventing HSPCs from loss of expansion and premature differentiation into myeloid lineage. Concomitantly, loss of Atf7ip or Setdb1 derepresses retrotransposons that instigate the viral sensor Mda5/Rig-I like receptor (RLR) signaling, leading to stress-driven myelopoiesis and inflammation. We find that ATF7IP or SETDB1 depletion represses human leukemic cell growth and induces myeloid differentiation with retrotransposon-triggered inflammation. These findings establish that Atf7ip/Setdb1-mediated H3K9me3 deposition constitutes a genome-wide checkpoint that impedes the myeloid potential and maintains HSPC stemness for diverse blood cell production, providing unique insights into potential intervention in hematological malignancy.


Assuntos
Células-Tronco Hematopoéticas , Histona-Lisina N-Metiltransferase , Peixe-Zebra , Animais , Humanos , Diferenciação Celular , Linhagem da Célula , Hematopoese , Células-Tronco Hematopoéticas/patologia , Histona-Lisina N-Metiltransferase/genética , Inflamação/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
2.
Cell Discov ; 8(1): 24, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35256606

RESUMO

Articular cartilage repair and regeneration is an unmet clinical need because of the poor self-regeneration capacity of the tissue. In this study, we found that the expression of prostaglandin E receptor 4 (PTGER4 or EP4) was largely increased in the injured articular cartilage in both humans and mice. In microfracture (MF) surgery-induced cartilage defect (CD) and destabilization of the medial meniscus (DMM) surgery-induced CD mouse models, cartilage-specific deletion of EP4 remarkably promoted tissue regeneration by enhancing chondrogenesis and cartilage anabolism, and suppressing cartilage catabolism and hypertrophy. Importantly, knocking out EP4 in cartilage enhanced stable mature articular cartilage formation instead of fibrocartilage, and reduced joint pain. In addition, we identified a novel selective EP4 antagonist HL-43 for promoting chondrocyte differentiation and anabolism with low toxicity and desirable bioavailability. HL-43 enhanced cartilage anabolism, suppressed catabolism, prevented fibrocartilage formation, and reduced joint pain in multiple pre-clinical animal models including the MF surgery-induced CD rat model, the DMM surgery-induced CD mouse model, and an aging-induced CD mouse model. Furthermore, HL-43 promoted chondrocyte differentiation and extracellular matrix (ECM) generation, and inhibited matrix degradation in human articular cartilage explants. At the molecular level, we found that HL-43/EP4 regulated cartilage anabolism through the cAMP/PKA/CREB/Sox9 signaling. Together, our findings demonstrate that EP4 can act as a promising therapeutic target for cartilage regeneration and the novel EP4 antagonist HL-43 has the clinical potential to be used for cartilage repair and regeneration.

3.
Cell Metab ; 33(10): 2021-2039.e8, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34508696

RESUMO

Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT. We found that ccRCC cells secrete parathyroid-hormone-related protein (PTHrP) to promote the browning of PAT by PKA activation, while PAT-mediated thermogenesis results in the release of excess lactate to enhance ccRCC growth, invasion, and metastasis. Further, tyrosine kinase inhibitors (TKIs) extensively used in the treatment of ccRCC enhanced this vicious cycle of ccRCC-PAT communication by promoting the browning of PAT. However, if this cross-communication was short circuited by the pharmacological suppression of adipocyte browning via H89 or KT5720, the anti-tumor efficacy of the TKI, sunitinib, was enhanced. These results suggest that ccRCC-PAT cross-communication has important clinical relevance, and use of combined therapy holds great promise in enhancing the efficacy of TKIs.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Adipócitos/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Renais/patologia , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Termogênese
4.
Int J Mol Sci ; 22(1)2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33383974

RESUMO

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch's membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Calcinose/genética , Calcinose/patologia , Fibrose/genética , Fibrose/patologia , Proteínas de Peixe-Zebra/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Olho/metabolismo , Olho/patologia , Predisposição Genética para Doença , Mutação , Miocárdio/metabolismo , Miocárdio/patologia , Vitamina K/metabolismo , Vitamina K/farmacologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
5.
Cell Res ; 29(11): 895-910, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31501519

RESUMO

The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a (VEGFA) has been commonly recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in mice. In tumor models, CDS2 deficiency enhanced the level of tumor-secreted VEGFA, which in-turn trapped tumors into a VEGFA-induced vessel regression situation, leading to suppression of tumor growth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence of CDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression.


Assuntos
Diacilglicerol Colinofosfotransferase/fisiologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , Nucleotidiltransferases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Linhagem Celular Tumoral , Diacilglicerol Colinofosfotransferase/genética , Células Endoteliais/enzimologia , Humanos , Melanoma Experimental , Camundongos , Camundongos Knockout , Nucleotidiltransferases/genética , Fator A de Crescimento do Endotélio Vascular/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
6.
J Genet Genomics ; 44(10): 483-492, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29037991

RESUMO

Vascular endothelial growth factor A (Vegfa) signaling regulates vascular development during embryogenesis and organ formation. However, the signaling mechanisms that govern the formation of various arteries/veins in various tissues are incompletely understood. In this study, we utilized transcription activator-like effector nuclease (TALEN) to generate zebrafish vegfaa mutants. vegfaa-/- embryos are embryonic lethal, and display a complete loss of the dorsal aorta (DA) and expansion of the cardinal vein. Activation of Vegfa signaling expands the arterial cell population at the expense of venous cells during vasculogenesis of the axial vessels in the trunk. Vegfa signaling regulates endothelial cell (EC) proliferation after arterial-venous specification. Vegfa deficiency and overexpression inhibit the formation of tip cell filopodia and interfere with the pathfinding of intersegmental vessels (ISVs). In the head vasculature, vegfaa‒/‒ causes loss of a pair of mesencephalic veins (MsVs) and central arteries (CtAs), both of which usually develop via sprouting angiogenesis. Our results indicate that Vegfa signaling induces the formation of the DA at the expense of the cardinal vein during the trunk vasculogenesis, and that Vegfa is required for the angiogenic formation of MsVs and CtAs in the brain. These findings suggest that Vegfa signaling governs the formation of diverse arteries/veins by distinct cellular mechanisms in vertebrate vasculatures.


Assuntos
Artérias/embriologia , Neovascularização Fisiológica , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Veias/embriologia , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Encéfalo/irrigação sanguínea , Encéfalo/embriologia , Desenvolvimento Embrionário , Mutação , Pseudópodes/metabolismo , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética
7.
Nat Commun ; 8(1): 87, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28729659

RESUMO

Noncompaction cardiomyopathy is characterized by the presence of extensive trabeculations, which could lead to heart failure and malignant arrhythmias. How trabeculations resolve to form compact myocardium is poorly understood. Elucidation of this process is critical to understanding the pathophysiology of noncompaction disease. Here we use genetic lineage tracing to mark the Nppa+ or Hey2+ cardiomyocytes as trabecular and compact components of the ventricular wall. We find that Nppa+ and Hey2+ cardiomyocytes, respectively, from the endocardial and epicardial zones of the ventricular wall postnatally. Interposed between these two postnatal layers is a hybrid zone, which is composed of cells derived from both the Nppa+ and Hey2+ populations. Inhibition of the fetal Hey2+ cell contribution to the hybrid zone results in persistence of excessive trabeculations in postnatal heart. Our findings indicate that the expansion of Hey2+ fetal compact component, and its contribution to the hybrid myocardial zone, are essential for normal formation of the ventricular walls.Fetal trabecular muscles in the heart undergo a poorly described morphogenetic process that results into a solidified compact myocardium after birth. Tian et al. show that cardiomyocytes in the fetal compact layer also contribute to this process, forming a hybrid myocardial zone that is composed of cells derived from both trabecular and compact layers.


Assuntos
Cardiomiopatias/embriologia , Ventrículos do Coração/embriologia , Animais , Animais Recém-Nascidos , Fator Natriurético Atrial , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cardiomiopatias/congênito , Cardiomiopatias/metabolismo , Linhagem da Célula , Coração/embriologia , Coração/crescimento & desenvolvimento , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/metabolismo , Ventrículos do Coração/crescimento & desenvolvimento , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Tipo C/metabolismo , Organogênese , Precursores de Proteínas/metabolismo , Proteínas Repressoras/metabolismo
8.
Int J Mol Sci ; 18(2)2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28230770

RESUMO

Vascular endothelial growth factor A (Vegfa) signaling regulates cardiovascular development. However, the cellular mechanisms of Vegfa signaling in early cardiogenesis remain poorly understood. The present study aimed to understand the differential functions and mechanisms of Vegfa signaling in cardiac development. A loss-of-function approach was utilized to study the effect of Vegfa signaling in cardiogenesis. Both morphants and mutants for vegfaa display defects in cardiac looping and chamber formation, especially the ventricle. Vegfa regulates the heart morphogenesis in a dose-dependent manner. Furthermore, the initial fusion of the bilateral myocardium population is delayed rather than endocardium. The results demonstrate that Vegfa signaling plays a direct impact on myocardium fusion, indicating that it is the initial cause of the heart defects. The heart morphogenesis is regulated by Vegfa in a dose-dependent manner, and later endocardium defects may be secondary to impaired myocardium-endocardium crosstalk.


Assuntos
Coração/embriologia , Miocárdio/metabolismo , Organogênese/genética , Fator A de Crescimento do Endotélio Vascular/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Animais , Proliferação de Células , Regulação da Expressão Gênica no Desenvolvimento , Morfogênese/genética , Mutação , Miócitos Cardíacos/metabolismo , Fenótipo , Fator A de Crescimento do Endotélio Vascular/deficiência , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
J Biol Chem ; 288(47): 34041-34051, 2013 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-24106267

RESUMO

The Hippo tumor suppressor pathway plays important roles in organ size control through Lats1/2 mediated phosphorylation of the YAP/TAZ transcription co-activators. However, YAP/TAZ independent functions of the Hippo pathway are largely unknown. Here we report a novel role of the Hippo pathway in angiogenesis. Angiomotin p130 isoform (AMOTp130) is phosphorylated on a conserved HXRXXS motif by Lats1/2 downstream of GPCR signaling. Phosphorylation disrupts AMOT interaction with F-actin and correlates with reduced F-actin stress fibers and focal adhesions. Furthermore, phosphorylation of AMOT by Lats1/2 inhibits endothelial cell migration in vitro and angiogenesis in zebrafish embryos in vivo. Thus AMOT is a direct substrate of Lats1/2 mediating functions of the Hippo pathway in endothelial cell migration and angiogenesis.


Assuntos
Actinas/metabolismo , Movimento Celular/fisiologia , Embrião não Mamífero/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Actinas/genética , Motivos de Aminoácidos , Angiomotinas , Animais , Células COS , Chlorocebus aethiops , Embrião não Mamífero/citologia , Adesões Focais/genética , Adesões Focais/metabolismo , Células HEK293 , Via de Sinalização Hippo , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Proteínas dos Microfilamentos , Proteínas Serina-Treonina Quinases/genética , Serina-Treonina Quinase 3 , Proteínas Supressoras de Tumor/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
11.
J Biol Chem ; 288(31): 22207-18, 2013 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-23766510

RESUMO

The ABC transporter ABCC4 is recognized as an ATP-dependent exporter of endogenous substances as well as an increasing variety of anionic chemotherapeutics. A loss-of-function variant of zebrafish Abcc4 was identified with a single amino acid substitution in the cytoplasmic loop T804M. Because this substituted amino acid is highly conserved among ABCC4 orthologs and is located in cytoplasmic loop 3 (CL3), we investigated the impact of this mutation on human and zebrafish Abcc4 expression. We demonstrate that zebrafish Abcc4 T804M or human ABCC4 T796M exhibit substantially reduced expression, coupled with impaired plasma membrane localization. To understand the molecular basis for the localization defect, we developed a homology model of zebrafish Abcc4. The homology model suggested that the bulky methionine substitution disrupted side-chain contacts. Molecular dynamic simulations of a fragment of human or zebrafish CL3 containing a methionine substitution indicated altered helicity coupled with reduced thermal stability. Trifluoroethanol challenge coupled with circular dichroism revealed that the methionine substitution disrupted the ability of this fragment of CL3 to readily form an α-helix. Furthermore, expression and plasma membrane localization of these mutant ABCC4/Abcc4 proteins are mostly rescued by growing cells at subphysiological temperatures. Because the cystic fibrosis transmembrane conductance regulator (ABCC7) is closely related to ABCC4, we extended this by engineering certain pathogenic CFTR-CL3 mutations, and we showed they destabilized human and zebrafish ABCC4. Altogether, our studies provide the first evidence for a conserved domain in CL3 of ABCC4 that is crucial in ensuring its proper plasma membrane localization.


Assuntos
Citoplasma/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Filogenia , Sequência de Aminoácidos , Animais , Linhagem Celular , Humanos , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Células NIH 3T3 , Homologia de Sequência de Aminoácidos , Peixe-Zebra
12.
Circ Res ; 112(4): 606-17, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23283723

RESUMO

RATIONALE: Mutagenesis screening is a powerful genetic tool for probing biological mechanisms underlying vertebrate development and human diseases. However, the increased colony management efforts in vertebrates impose a significant challenge for identifying genes affecting a particular organ, such as the heart, especially those exhibiting adult phenotypes on depletion. OBJECTIVE: We aim to develop a facile approach that streamlines colony management efforts via enriching cardiac mutants, which enables us to screen for adult phenotypes. METHODS AND RESULTS: The transparency of the zebrafish embryos enabled us to score 67 stable transgenic lines generated from an insertional mutagenesis screen using a transposon-based protein trapping vector. Fifteen lines with cardiac monomeric red fluorescent protein reporter expression were identified. We defined the molecular nature for 10 lines and bred them to homozygosity, which led to the identification of 1 embryonic lethal, 1 larval lethal, and 1 adult recessive mutant exhibiting cardiac hypertrophy at 1 year of age. Further characterization of these mutants uncovered an essential function of methionine adenosyltransferase II, α a (mat2aa) in cardiogenesis, an essential function of mitochondrial ribosomal protein S18B (mrps18b) in cardiac mitochondrial homeostasis, as well as a function of DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b) in adult cardiac hypertrophy. CONCLUSIONS: We demonstrate that transposon-based gene trapping is an efficient approach for identifying both embryonic and adult recessive mutants with cardiac expression. The generation of a zebrafish insertional cardiac mutant collection shall facilitate the annotation of a vertebrate cardiac genome, as well as enable heart-based adult screens.


Assuntos
Cardiomegalia/genética , Perfilação da Expressão Gênica , Genes Recessivos , Testes Genéticos/métodos , Mutagênese Insercional , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Cruzamento , Elementos de DNA Transponíveis/genética , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Genes Letais , Genes Reporter , Vetores Genéticos/genética , Genótipo , Coração/embriologia , Proteínas Luminescentes/análise , Proteínas Luminescentes/genética , Especificidade de Órgãos , Fenótipo , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/fisiologia , Proteína Vermelha Fluorescente
13.
J Neurochem ; 96(5): 1423-40, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16464238

RESUMO

Gamma-secretase cleavage, mediated by a complex of presenilin, presenilin enhancer (Pen-2), nicastrin, and Aph-1, is the final proteolytic step in generating amyloid beta protein found in brains of Alzheimer's disease patients and Notch intracellular domain critical for proper neuronal development. Here, we employ the zebrafish model to study the role of Pen-2 in neuronal survival. We found that (i) knockdown of Pen-2 using antisense morpholino led to a reduction of islet-1 positive neurons, (ii) Notch signaling was reduced in embryos lacking Pen-2 or other gamma-secretase components, (iii) neuronal loss in Pen-2 knockdown embryos is not as a result of a lack of neuronal precursor cells or cell proliferation, (iv) absence of Pen-2 caused massive apoptosis in the whole animal, which could be suppressed by simultaneous knockdown of the tumor suppressor p53, (v) loss of islet-1 or acetylated tubulin positive neurons in Pen-2 knockdown embryos could be partially rescued by knockdown of p53. Our results demonstrate that knockdown of Pen-2 directly induces a p53-dependent apoptotic pathway that contributes to neuronal loss and suggest that Pen-2 plays an important role in promoting neuronal cell survival and protecting from apoptosis in vivo.


Assuntos
Apoptose/genética , Proteínas de Peixes/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Membrana/fisiologia , Neurônios/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Doença de Alzheimer , Animais , Animais Geneticamente Modificados , Northern Blotting , Western Blotting/métodos , Padronização Corporal/efeitos dos fármacos , Padronização Corporal/genética , Contagem de Células/métodos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Embrião não Mamífero , Proteínas de Peixes/química , Proteínas de Peixes/deficiência , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Marcação In Situ das Extremidades Cortadas/métodos , Indóis , Proteínas de Membrana/química , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Presenilina-2 , RNA Mensageiro/metabolismo , Receptores Notch/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Proteína Supressora de Tumor p53/química , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/metabolismo
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