RESUMEN
Haematopoietic stem and progenitor cells (HSPCs) have been the focus of developmental and regenerative studies, yet our understanding of the signalling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the Facilitates chromatin transcription (FACT) complex, is required for HSPC formation. Zebrafish supt16h mutants express reduced levels of Notch-signalling components, genes essential for HSPC development, due to abrogated transcription. Whereas global chromatin accessibility in supt16h mutants is not substantially altered, we observe a specific increase in p53 accessibility, causing an accumulation of p53. We further demonstrate that p53 influences expression of the Polycomb-group protein PHC1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues the loss of both Notch and HSPC phenotypes in supt16h mutants. Our results highlight a relationship between supt16h, p53 and phc1 to specify HSPCs via modulation of Notch signalling.
Asunto(s)
Proteínas de Ciclo Celular/genética , Células Madre Hematopoyéticas/metabolismo , Receptores Notch/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Proteínas de Ciclo Celular/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Ontología de Genes , Células Madre Hematopoyéticas/citología , Mutación , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Receptores Notch/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Proteína p53 Supresora de Tumor/metabolismo , Pez Cebra/embriología , Pez Cebra/crecimiento & desarrollo , Proteínas de Pez Cebra/metabolismoRESUMEN
BACKGROUND: Left-sided gallbladder without situs viscerum inversus (LSG-woSVI) is a rare congenital anomaly. Clinical features and routine presurgical imaging could miss the anomalous position, thereby producing complications during surgery. Laparoscopic cholecystectomy can be performed safely, but the risk of bile duct injury (BDI) is greater than in cholecystectomy of the orthotopic gallbladder. We present a retrospective review of all scientific literature for diagnosed cases of LSG-woSVI undergoing cholecystectomy from 1996 to 2014. Our objectives were to outline empirical top tips for a safe cholecystectomy in incidentally diagnosed LSG-woSVI. METHODS: We carried a comprehensive search of PubMed using medical subject headings "left-sided gallbladder," "right-sided ligamentum teres" "situs viscerun inversus," "preoperative diagnoses," "cholecystectomy," and "bile duct injury." We considered a classification of the LSG-woSVI in 2 groups: True LSG-woSVI and LSG-woSVI in patients with right-sided ligamentum teres. RESULTS: Our retrospective review revealed 55 cases of LSG-woSVI. The mean age was 51 years ±17 SD, male/female ratio was 2:1, clinical presentation was pain in the right upper abdominal quadrant in 75.5%, preoperative diagnosis was reached in 16.3%, True LSG was diagnosed in 83%, acute cholecystitis was found in 50%, laparoscopic cholecystectomy was performed in 79.6%, fundus-first dissection technique was used in 16.7%, intraoperative cholangiography was performed in 39.1%, and BDI occurred in 7.3% of the reported cases. CONCLUSIONS: Increased awareness of the anatomic aberrations in LSG-woSVI associated with improved preoperative diagnosis and a good knowledge about safe surgical techniques for cholecystectomy could indubitably reduce the incidence of BDI.
Asunto(s)
Colecistectomía Laparoscópica/métodos , Enfermedades de la Vesícula Biliar/cirugía , Vesícula Biliar/anomalías , Conductos Biliares/lesiones , Colecistitis Aguda/cirugía , Servicio de Urgencia en Hospital/estadística & datos numéricos , Tratamiento de Urgencia/métodos , Estudios de Factibilidad , Femenino , Vesícula Biliar/cirugía , Humanos , Complicaciones Intraoperatorias/prevención & control , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Haematopoietic stem cells (HSCs) derive from haemogenic endothelial cells of the primitive dorsal aorta (DA) during vertebrate embryogenesis. The molecular mechanisms governing this unique endothelial to haematopoietic transition remain unclear. Here, we demonstrate a novel requirement for fibroblast growth factor (FGF) signalling in HSC emergence. This requirement is non-cell-autonomous, and acts within the somite to bridge the Wnt and Notch signalling pathways. We previously demonstrated that Wnt16 regulates the somitic expression of two Notch ligands, deltaC (dlc) and deltaD (dld), whose combined function is required for HSC fate. How Wnt16 connects to Notch function has remained an open question. Our current studies demonstrate that FGF signalling, via FGF receptor 4 (Fgfr4), mediates a signal-transduction pathway between Wnt16 and Dlc, but not Dld, to regulate HSC specification. Our findings demonstrate that FGF signalling acts as a key molecular relay within the developmental HSC niche to instruct HSC fate.
