Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development

Abstract

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 17β‐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.

Loss of the RNA-binding protein Rbm15 disrupts liver maturation in zebrafish

“…The Hippo/ YAP pathway is crucial for liver size control; hyper-YAP1 activity in the liver stimulates hepatocyte and cholangiocyte specification, whereas loss of YAP1 decreases hepatocyte survival and impairs biliary duct morphogenesis (12). Notch signaling and esr2b are also involved in hepatocyte differentiation and bile duct formation (13,14). Numerous transcription factors govern cell fate choices.…”

Estrogen signaling in development: recent insights from the zebrafish

“…Further analysis revealed that E2 signaling mediated by Esr2b operates upstream of essential distal transcription factors Irx3b and its target Irx1a (Wesselman et al, 2023). Taken together, Esr2b seems to regulate cell fate choice in multiple zebrafish tissues, as a similar phenotype was observed in liver tissue (Wesselman et al, 2023;Chaturantabut et al, 2020).…”

“…Gorelick and Halpern, 2011;Chaturantabut et al, 2020). esr2a is also expressed in neuromast cells, and esr2a and esr2b are expressed more in the intestine (Froehlicher et al, 2009;Menuet et al, 2002).…”

“…For example, the adult liver expresses esr1, esr2a and esr2b as assessed by reverse transcription polymerase chain reaction (Menuet et al, 2002). In the developing zebrafish liver, esr2b is detectable by whole mount in situ hybridization (WISH) at 72 hpf, but decreases shortly thereafter (Bertrand et al, 2007;Chaturantabut et al, 2020). By 96 hpf, gper1 is robustly expressed in the liver, as detected by WISH (Chaturantabut et al, 2019).…”

Oestradiol promotes the intrahepatic bile duct development of C57BL/6CrSlc mice during embryonic period via Notch signalling pathway

“…Liver is known to be a target organ of oestradiol, which is crucial for liver regeneration after partial hepatectomy 33 and liver growth in mammalian neonates. 34 However, there are different opinions as to the mechanism of oestradiol promoting the liver growth. Uebi, T et al said that oestradiol controls the hepatocyte proliferation.…”