RESUMO
Suppressor of cytokine signaling 1 (SOCS1) has been shown to play important roles in the immune system. It acts as a key negative regulator of signaling via receptors for IFNs and other cytokines controlling T cell development, as well as Toll receptor signaling in macrophages and other immune cells. To gain further insight into SOCS1, we have identified and characterized the zebrafish socs1 gene, which exhibited sequence and functional conservation with its mammalian counterparts. Initially maternally derived, the socs1 gene showed early zygotic expression in mesodermal structures, including the posterior intermediate cell mass, a site of primitive hematopoiesis. At later time points, expression was seen in a broad anterior domain, liver, notochord, and intersegmental vesicles. Morpholino-mediated knockdown of socs1 resulted in perturbation of specific hematopoietic populations prior to the commencement of lymphopoiesis, ruling out T cell involvement. However, socs1 knockdown also lead to a reduction in the size of the developing thymus later in embryogenesis. Zebrafish SOCS1 was shown to be able to interact with both zebrafish Jak2a and Stat5.1 in vitro and in vivo. These studies demonstrate a conserved role for SOCS1 in T cell development and suggest a novel T cell-independent function in embryonic myelopoiesis mediated, at least in part, via its effects on receptors using the Jak2-Stat5 pathway.
Assuntos
Mielopoese , Proteínas Supressoras da Sinalização de Citocina/genética , Linfócitos T/metabolismo , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação/genética , Clonagem Molecular , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Hibridização In Situ , Dados de Sequência Molecular , Filogenia , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Tirosina Quinases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT5/metabolismo , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/classificação , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/classificação , Proteínas de Peixe-Zebra/metabolismoRESUMO
Most severe congenital neutropenia (SCN) cases possess constitutive neutrophil elastase mutations; a smaller cohort has acquired mutations truncating the granulocyte colony-stimulating factor receptor (G-CSF-R). We have described a case with constitutive extracellular G-CSF-R mutation hyporesponsive to ligand. Here we report two independent acquired G-CSF-R truncation mutations and a novel constitutive neutrophil elastase mutation in this patient. Co-expression of a truncated receptor chain restored STAT5 signalling responses of the extracellular G-CSF-R mutant, while constitutively-active STAT5 enhanced its proliferative capacity. These data add to our knowledge of SCN and further highlight the importance of STAT5 in mediating proliferative responses to G-CSF.
Assuntos
Elastase de Leucócito/genética , Mutação/genética , Neutropenia/congênito , Receptores de Fator Estimulador de Colônias de Granulócitos/genética , Criança , Análise Mutacional de DNA , Humanos , Neutropenia/enzimologia , Neutropenia/genética , Reação em Cadeia da Polimerase , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator de Transcrição STAT5/genética , Serina Endopeptidases/genéticaRESUMO
The complexity of multicellular organisms is dependent on systems enabling cells to respond to specific stimuli. Cytokines and their receptors are one such system, whose perturbation can lead to a variety of disease states. This review represents an overview of our current understanding of the cytokine receptors, Janus kinases (Jaks), Signal transducers and activators of transcription (Stats) and Suppressors of cytokine signaling (Socs), focussing on their contribution to diseases of an immune or hematologic nature.
Assuntos
Doenças Hematológicas/imunologia , Doenças do Sistema Imunitário/imunologia , Janus Quinases/metabolismo , Receptores de Citocinas/metabolismo , Fatores de Transcrição STAT/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Humanos , Transdução de SinaisRESUMO
BACKGROUND: Lying downstream of a myriad of cytokine receptors, the Janus kinase (JAK)-Signal transducer and activator of transcription (STAT) pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP), Protein inhibitors against Stats (PIAS), and Suppressor of cytokine signaling (SOCS) proteins across a diverse range of organisms. RESULTS: Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components. CONCLUSION: Diversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.
Assuntos
Sistema Imunitário/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Evolução Molecular , Humanos , Janus Quinases/classificação , Janus Quinases/genética , Modelos Biológicos , Filogenia , Proteínas Inibidoras de STAT Ativados/classificação , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Inibidoras de STAT Ativados/metabolismo , Receptores Citoplasmáticos e Nucleares/classificação , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição STAT/classificação , Fatores de Transcrição STAT/genética , Proteínas Supressoras da Sinalização de Citocina/classificação , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , SinteniaRESUMO
The human RBMX gene was discovered recently through its homology to the spermatogenesis candidate gene RBMY. Its position on the human X chromosome suggests that it may be involved in X-linked mental retardation syndromes. However, to date there is scant information on the in vivo role of RBMX. To address this issue, we have isolated a zebrafish rbmx orthologue and characterized its embryonic expression pattern. Zebrafish rbmx is maternally expressed and then widely expressed in the embryo up to 24 hr postfertilization. In later stages of embryonic development, rbmx transcripts are localized predominantly in the brain, branchial arches, and liver primordium. The function of rbmx during embryonic development was examined by the use of an antisense morpholino targeting rbmx. The rbmx-morphants displayed an underdeveloped head and eyes, reduced body size, defective somite patterning, and absence of jaws. Furthermore, in the absence of functional rbmx, expression of specific markers for the fore- and hindbrain (otx2, krox20) was severely reduced. These studies demonstrate for the first time that rbmx is required for normal embryonic development, in particular of the brain, consistent with a role in X-linked mental retardation.