RESUMEN
BACKGROUND AND AIMS: During liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver required to maintain organismal homeostasis. The developmental cues controlling the differentiation of committed progenitors into these cell types, however, are incompletely understood. Here, we discover an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. APPROACH AND RESULTS: Exposure of zebrafish embryos to 17ß-estradiol (E2) during liver development significantly decreased hepatocyte-specific gene expression, liver size, and hepatocyte number. In contrast, pharmacological blockade of estrogen synthesis or nuclear estrogen receptor (ESR) signaling enhanced liver size and hepatocyte marker expression. Transgenic reporter fish demonstrated nuclear ESR activity in the developing liver. Chemical inhibition and morpholino knockdown of nuclear estrogen receptor 2b (esr2b) increased hepatocyte gene expression and blocked the effects of E2 exposure. esr2b-/- mutant zebrafish exhibited significantly increased expression of hepatocyte markers with no impact on liver progenitors, other endodermal lineages, or vasculature. Significantly, E2-stimulated Esr2b activity promoted biliary epithelial differentiation at the expense of hepatocyte fate, whereas loss of esr2b impaired biliary lineage commitment. Chemical and genetic epistasis studies identified bone morphogenetic protein (BMP) signaling as a mediator of the estrogen effects. The divergent impact of estrogen on hepatobiliary fate was confirmed in a human hepatoblast cell line, indicating the relevance of this pathway for human liver development. CONCLUSIONS: Our studies identify E2, esr2b, and downstream BMP activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant clinical implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy.
Asunto(s)
Sistema Biliar/embriología , Estradiol/metabolismo , Receptor beta de Estrógeno/metabolismo , Regulación del Desarrollo de la Expresión Génica , Hígado/embriología , Proteínas de Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente , Sistema Biliar/citología , Sistema Biliar/metabolismo , Diferenciación Celular/genética , Línea Celular , Embrión no Mamífero , Estradiol/administración & dosificación , Receptor beta de Estrógeno/genética , Femenino , Técnicas de Silenciamiento del Gen , Hepatocitos/fisiología , Hígado/citología , Hígado/metabolismo , Masculino , Modelos Animales , Morfolinos/administración & dosificación , Morfolinos/genética , Transducción de Señal/genética , Células Madre/fisiología , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
A laboratory zebrafish colony developed red masses, predominantly under the jaw, in a significant portion of the population. The masses were diagnosed histopathologically as thyroid follicular hyperplasia, adenoma, or carcinoma in accordance with published morphologic criteria. After switching to a higher iodine brand of salt used to maintain a low level of salinity within the water system and a small diet change, the thyroid lesions regressed dramatically. Within 5 months the masses were no longer grossly visible. At the population level, external evaluations and histopathological assessments of whole-body sections document a regression in the prevalence of thyroid neoplasia and hyperplasia to normal thyroid conformation by 11 months after salt change. These findings suggest that a wide range of proliferative thyroid lesions, including neoplasms, in zebrafish may be hormone-dependent, even following lesion development. In addition, these results suggest that zebrafish have an adaptive ability to absorb iodine from water and food, which should be considered in discussions to standardize diets and when describing environmental parameters in publications.
Asunto(s)
Adenoma/veterinaria , Hiperplasia/veterinaria , Yodo/administración & dosificación , Yodo/deficiencia , Neoplasias de la Tiroides/veterinaria , Pez Cebra , Adenoma/etiología , Adenoma/patología , Adenoma/prevención & control , Animales , Dieta , Femenino , Hiperplasia/etiología , Hiperplasia/patología , Hiperplasia/prevención & control , Masculino , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/patología , Neoplasias de la Tiroides/prevención & controlRESUMEN
Hematopoietic stem and progenitor cell (HSPC) specification is regulated by numerous defined factors acting locally within the hemogenic niche; however, it is unclear whether production can adapt to fluctuating systemic needs. Here we show that the CNS controls embryonic HSPC numbers via the hypothalamic-pituitary-adrenal/interrenal (HPA/I) stress response axis. Exposure to serotonin or the reuptake inhibitor fluoxetine increased runx1 expression and Flk1(+)/cMyb(+) HSPCs independent of peripheral innervation. Inhibition of neuronal, but not peripheral, tryptophan hydroxlyase (Tph) persistently reduced HSPC number. Consistent with central HPA/I axis induction and glucocorticoid receptor (GR) activation, GR agonists enhanced, whereas GR loss diminished, HSPC formation. Significantly, developmental hypoxia, as indicated by Hif1α function, induced the HPA/I axis and cortisol production. Furthermore, Hif1α-stimulated HSPC enhancement was attenuated by neuronal tph or GR loss. Our data establish that embryonic HSC production responds to physiologic stress via CNS-derived serotonin synthesis and central feedback regulation to control HSC numbers.