Id2a is required for hepatic outgrowth during liver development in zebrafish

Khaliq, Mehwish; Choi, Tae-Young; So, Juhoon; Shin, Donghun

doi:10.1016/j.mod.2015.05.001

Cited by 8 publications

(12 citation statements)

References 70 publications

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“…Using a morpholino-mediated knockdown approach, we previously reported that during liver development Id2a positively regulates hepatic outgrowth through hepatoblast proliferation and survival. (31) However, we found that during BEC-driven liver regeneration Id2a negatively regulates the proliferation of newly generated BECs. Although we did not detect any developmental defects in the id2a -/mutants, inconsistent with the morpholino results, this discrepancy might be explained by the genetic compensations that can occur in mutants but not in morphants.…”

Section: Discussionmentioning

confidence: 67%

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Bone morphogenetic protein signaling governs biliary‐driven liver regeneration in zebrafish through tbx2b and id2a

et al. 2017

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Upon mild liver injury, new hepatocytes originate from pre-existing hepatocytes. However, if hepatocyte proliferation is impaired, a manifestation of severe liver injury, biliary epithelial cells (BECs) contribute to new hepatocytes through BEC dedifferentiation into liver progenitor cells (LPCs), also termed oval cells or hepatoblast-like cells (HB-LCs), and subsequent differentiation into hepatocytes. Despite the identification of several factors regulating BEC dedifferentiation and activation, little is known about factors involved in the regulation of LPC differentiation into hepatocytes during liver regeneration. Using a zebrafish model of near-complete hepatocyte ablation, we here show that Bmp signaling is required for BEC conversion to hepatocytes, particularly for LPC differentiation into hepatocytes. We found that severe liver injury led to the upregulation of genes involved in Bmp signaling, including smad5, tbx2b, and id2a, in the liver. Bmp suppression did not block BEC dedifferentiation into HB-LCs; however, the differentiation of HB-LCs into hepatocytes was impaired due to the maintenance of HB-LCs in an undifferentiated state. Later Bmp suppression did not affect HB-LC differentiation, but increased BEC number through proliferation. Notably, smad5, tbx2b, and id2a mutants exhibited similar liver regeneration defects as those observed in Bmp-suppressed livers. Moreover, BMP2 addition promoted the differentiation of a murine LPC cell line into hepatocytes in vitro. Conclusions: Bmp signaling regulates BEC-driven liver regeneration via smad5, tbx2b and id2a: it regulates HB-LC differentiation into hepatocytes via tbx2b and BEC proliferation via id2a. Our findings provide insights into promoting innate liver regeneration as a novel therapy.

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Section: Discussionmentioning

confidence: 67%

“…Using a morpholino‐mediated knockdown approach, we previously reported that during liver development Id2a positively regulates hepatic outgrowth through hepatoblast proliferation and survival . However, we found that during BEC‐driven liver regeneration Id2a negatively regulates the proliferation of newly generated BECs.…”

Section: Discussionmentioning

confidence: 77%

Bone morphogenetic protein signaling governs biliary‐driven liver regeneration in zebrafish through tbx2b and id2a

et al. 2017

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“…Hence, we analyzed the function of Id2, which has been shown to suppress the function of Neurod [ 19 ] and an immediate target of Bmp signaling [ 18 ]. Zebrafish have two id2 genes: id2a and id2b [ 53 ]. Only id2a is expressed in the liver from 30 hpf onwards [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

“…Zebrafish have two id2 genes: id2a and id2b [ 53 ]. Only id2a is expressed in the liver from 30 hpf onwards [ 53 ]. We conducted loss-of-function analyses using published id2a MO [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration

Cui

Campo

et al. 2016

PLoS Genet

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The liver and pancreas originate from overlapping embryonic regions, and single-cell lineage tracing in zebrafish has shown that Bone morphogenetic protein 2b (Bmp2b) signaling is essential for determining the fate of bipotential hepatopancreatic progenitors towards the liver or pancreas. Despite its pivotal role, the gene regulatory networks functioning downstream of Bmp2b signaling in this process are poorly understood. We have identified four and a half LIM domains 1b (fhl1b), which is primarily expressed in the prospective liver anlage, as a novel target of Bmp2b signaling. fhl1b depletion compromised liver specification and enhanced induction of pancreatic cells from endodermal progenitors. Conversely, overexpression of fhl1b favored liver specification and inhibited induction of pancreatic cells. By single-cell lineage tracing, we showed that fhl1b depletion led lateral endodermal cells, destined to become liver cells, to become pancreatic cells. Reversely, when fhl1b was overexpressed, medially located endodermal cells, fated to differentiate into pancreatic and intestinal cells, contributed to the liver by directly or indirectly modulating the discrete levels of pdx1 expression in endodermal progenitors. Moreover, loss of fhl1b increased the regenerative capacity of β-cells by increasing pdx1 and neurod expression in the hepatopancreatic ductal system. Altogether, these data reveal novel and critical functions of Fhl1b in the hepatic versus pancreatic fate decision and in β-cell regeneration.

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“…In parallel, Id2a maintains hepatoblast number(Khaliq et al, 2015). Ida2 controls hepatoblast proliferation and also promotes cell survival independent of proliferation through two downstream targets: Anxa4 and Nexin7 (Zhang et al, 2014).…”

Section: Liver Development: Zebrafish As a Paradigmmentioning

confidence: 99%

Making It New Again

Wang

Miller

Ober

et al. 2017

Current Topics in Developmental Biology

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The adult liver of most vertebrates is predominantly comprised of hepatocytes. However, these cells must work in concert with biliary, stellate, vascular, and immune cells to accomplish the vast array of hepatic functions required for physiological homeostasis. Our understanding of liver development was accelerated as zebrafish emerged as an ideal vertebrate system to study embryogenesis. Through work in zebrafish and other models, it is now clear that the cells in the liver develop in a coordinated fashion during embryogenesis through a complex yet incompletely understood set of molecular guidelines. Zebrafish research has uncovered many key players that govern the acquisition of hepatic potential, cell fate, and plasticity. Although rare, some hepatobiliary diseases-especially biliary atresia-are caused by developmental defects; we discuss how research using zebrafish to study liver development has informed our understanding of and approaches to liver disease. The liver can be injured in response to an array of stressors including viral, mechanical/surgical, toxin-induced, immune-mediated, or inborn defects in metabolism. The liver has thus evolved the capacity to efficiently repair and regenerate. We discuss the emerging field of using zebrafish to study liver regeneration and highlight recent advances where zebrafish genetics and imaging approaches have provided novel insights into how cell plasticity contributes to liver regeneration.

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Id2a is required for hepatic outgrowth during liver development in zebrafish

Cited by 8 publications

References 70 publications

Bone morphogenetic protein signaling governs biliary‐driven liver regeneration in zebrafish through tbx2b and id2a

Bone morphogenetic protein signaling governs biliary‐driven liver regeneration in zebrafish through tbx2b and id2a

Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration

Making It New Again

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