Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration.
Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration.
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DOI：
10.1371/journal.pgen.1005831
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发表时间：
2016-02
期刊：
影响因子：
4.5
通讯作者：
Shin CH
中科院分区：
文献类型：
--
作者：
Xu J;Cui J;Del Campo A;Shin CH
肝脏和胰腺起源于重叠的胚胎区，斑马鱼的单细胞谱系追踪表明骨形态发生蛋白2b(Bmp2b)信号对决定双潜能肝胰腺祖细胞向肝脏或胰腺的命运至关重要。尽管Bmp2b在这一过程中起着关键作用，但其下游的基因调控网络却知之甚少。我们已经确定了四个半LIM结构域1b(Fhl1b)，它主要在预期的肝脏原基中表达，是Bmp2b信号的新靶点。Fhl1b的耗尽损害了肝脏的规格，并促进了从内胚祖细胞向胰腺细胞的诱导。相反，fhl1b的过表达有利于肝脏的规范，并抑制胰腺细胞的诱导。通过单细胞谱系示踪，我们发现fhl1b缺失导致外侧内胚层细胞成为肝细胞，成为胰腺细胞。相反，当fhl1b过表达时，位于中间的内皮细胞注定要分化为胰腺和肠道细胞，通过直接或间接调节内皮祖细胞中PDX1的离散表达水平而对肝脏做出贡献。此外，Fhl1b的缺失通过增加肝胰管系统中PDX1和Neurd的表达，增加了β-细胞的再生能力。总之，这些数据揭示了Fhl1b在决定肝脏和胰腺命运以及在β细胞再生中的新的和关键的功能。谱系特异性的多能祖细胞在胚胎发育、成人组织再生和癌症等疾病中发挥着关键作用。骨形态发生蛋白(BMP)信号转导对于调节肝和胰腺这两个人体代谢的重要器官的细胞命运选择至关重要。通过对暴露于Bmp2b信号增强或降低的内皮组织的转录组谱分析，我们发现斑马鱼基因4.5LIM结构域1b(Fhl1b)是Bmp2b信号的新靶点。Fhl1b主要在预期的肝原区表达。功能丧失和功能获得分析表明，Fhl1b抑制了胰腺的规范，并诱导了肝脏。通过单细胞谱系追踪，我们发现fhl1b的缺失导致了从肝到胰腺的命运转换，而fhl1b的过表达则将胰腺祖细胞重新定向为肝细胞。在后期阶段，Fhl1b通过直接或间接调节肝胰管系统中PDX1和Neurd的表达来调节胰岛素分泌β细胞的再生。因此，我们的工作为BMP信号如何通过其新的靶点Fhl1b调控肝与胰腺的命运决定和β细胞再生提供了一个新的范例。
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. Lineage-specific multipotent progenitors play crucial roles in embryonic development, regeneration in adult tissues, and diseases such as cancer. Bone morphogenetic protein (Bmp) signaling is critical for regulating the cell fate choice of liver versus pancreas, two essential organs of body metabolism. Through transcriptome profiling of endodermal tissues exposed to increased or decreased Bmp2b signaling, we have discovered the zebrafish gene four and a half LIM domains 1b (fhl1b) as a novel target of Bmp2b signaling. fhl1b is primarily expressed in the prospective liver anlage. Loss- and gain-of-function analyses indicate that Fhl1b suppresses specification of the pancreas and induces the liver. By single-cell lineage tracing, we showed that depletion of fhl1b caused a liver-to-pancreas fate switch, while fhl1b overexpression redirected pancreatic progenitors to become liver cells. At later stages, Fhl1b regulates regeneration of insulin-secreting β-cells by directly or indirectly modulating pdx1 and neurod expression in the hepatopancreatic ductal system. Therefore, our work provides a novel paradigm of how Bmp signaling regulates the hepatic versus pancreatic fate decision and β-cell regeneration through its novel target Fhl1b.