Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development.
Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development.
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视黄酸在胰腺发育中起进化保守和双相作用。
DOI：
10.1016/j.ydbio.2014.07.021
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发表时间：
2014-10-01
影响因子：
2.7
通讯作者：
Parsons MJ
中科院分区：
文献类型：
--
作者：
Huang W;Wang G;Delaspre F;Vitery Mdel C;Beer RL;Parsons MJ
随着斑马鱼胰腺的发育成熟，产生激素的内分泌细胞从位于导管内的胰腺缺口反应细胞(PNC)分化出来。这些新的内分泌细胞形成称为次级(2°)胰岛的小簇。我们用斑马鱼幼体胰尾2°胰岛的形成作为β细胞新生的模型。药物抑制Notch信号导致内分泌性早熟分化，胰腺尾部提前出现2°胰岛。经过化学筛选，我们发现阻断维甲酸(RA)信号通路也会导致2°胰岛的诱导。相反，外源RA的加入阻断了Notch抑制引起的分化。在这份报告中，我们描述了这两条途径的相互作用。我们首先验证了通过RA和Notch配体的信号共同作用来调节胰腺前体细胞的分化。我们制作了一个转基因的RA报告，它证明了PNC通过规范的转录途径直接响应RA信号。接下来，使用遗传谱系追踪的方法，我们证明了这些祖细胞在RA信号被抑制后产生内分泌细胞。最后，使用细胞类型特异性可诱导的cre/lox系统抑制RA信号表明，RA信号在PNC中以细胞自主的方式作用于调节其分化。重要的是，RA抑制对内分泌形成的作用在进化上是保守的，正如在人类胰腺发育模型中人类胚胎干细胞的分化所表明的那样。综上所述，这些结果揭示了RA在胰腺发生中的双相作用。如前所述，RA最初在胚胎发育过程中起着至关重要的作用，因为它形成了内胚层的模式，并指定了胰腺区域。我们在这里揭示，在发育后期，RA参与负向调节胰腺前体细胞的进一步分化，并扩展发生这种分化的发育机制。
As the developing zebrafish pancreas matures, hormone-producing endocrine cells differentiate from pancreatic Notch-responsive cells (PNCs) that reside within the ducts. These new endocrine cells form small clusters known as secondary (2°) islets. We use the formation of 2° islets in the pancreatic tail of the larval zebrafish as a model of β-cell neogenesis. Pharmacological inhibition of Notch signaling leads to precocious endocrine differentiation and the early appearance of 2° islets in the tail of the pancreas. Following a chemical screen, we discovered that blocking the retinoic acid (RA)-signaling pathway also leads to the induction of 2° islets. Conversely, the addition of exogenous RA blocks the differentiation caused by Notch inhibition. In this report we characterize the interaction of these two pathways. We first verified that signaling via both RA and Notch ligands act together to regulate pancreatic progenitor differentiation. We produced a transgenic RA reporter, which demonstrated that PNCs directly respond to RA signaling through the canonical transcriptional pathway. Next, using a genetic lineage tracing approach, we demonstrated these progenitors produce endocrine cells following inhibition of RA signaling. Lastly, inhibition of RA signaling using a cell-type specific inducible cre/lox system revealed that RA signaling acts cell-autonomously in PNCs to regulate their differentiation. Importantly, the action of RA inhibition on endocrine formation is evolutionarily conserved, as shown by the differentiation of human embryonic stem cells in a model of human pancreas development. Together, these results revealed a biphasic function for RA in pancreatogenesis. As previously shown by others, RA initially plays an essential role during embryogenesis as it patterns the endoderm and specifies the pancreatic field. We reveal here that later in development RA is involved in negatively regulating the further differentiation of pancreatic progenitors and expands upon the developmental mechanisms by which this occurs.