确定性内胚层形成
中文名称
通路描述
哺乳动物胚胎的内胚层起源于两种不同的细胞群：前胃板期就存在的腹内胚层，以及由原肠胚细胞通过原肠胚前部侵入形成的确定性内胚层。侵入后，确定性内胚层细胞与腹内胚层细胞间插，形成胚胎内胚层，将发育为肠道及与肠道相关的内脏器官（如胰腺和肝脏）（参见 Lewis and Tam 2006, Nowotschin et al. 2019）。在圆盘状人类囊胚中，内胚层最初呈扁平上皮层，随后卷曲形成肠道。由于伦理考虑，关于原肠胚的研究主要在灵长类动物（例如 Bergmann et al. 2022）和干细胞（D'Amour et al. 2005，参见 Salehin et al. 2022）中进行，这些研究为人类胚胎的胚层形成提供了见解。确定性内胚层起源于原肠胚前部，该区域具有高水平的 NODAL 信号（源自 Vincent et al. 2003 的鼠胚胎推断）和较低的 BMP 信号（源自 Bachiller et al. 2000 的鼠胚胎推断）以及 Wnt 信号（源自 Mukhopadhyay et al. 2001 的鼠胚胎推断）。在鼠中，Eomesodermin（EOMES），其表达由 NODAL 信号通过 SMAD2 和 SMAD3 激活，对于形成中胚层和内胚层是必需的（Arnold et al. 2008）。在人类胚胎干细胞和鼠胚胎实验中表明，EOMES 是决定确定性内胚层的核心要素，通过激活转录因子如 FOXA2 和 SOX17 的表达来发挥作用，进而激活一系列内胚层基因（Teo et al. 2011, Chia et al. 2019）。当内胚层祖细胞进入原肠胚时，它们会在表面重新分布 E-cadherin（CDH1），这可能有助于将细胞分化为上皮层（源自 Viotti et al. 2014 的鼠同源物推断）。与中胚层不同，内胚层祖细胞不会经历完全的上皮 - 间质转化（EMT）（源自 Scheibner et al. 2021 的鼠胚胎和干细胞推断）。它们不将细胞粘附分子从 E-cadherin（CDH1）切换为 N-cadherin（CDH2），也不需要 EMT 转录因子 SNAI1（源自 Scheibner et al. 2021 的鼠同源物推断）。内胚层转录因子 FOXA2 可能抑制 EMT 活性（源自 Scheibner et al. 2021 的鼠同源物推断）。虽然没有单一标记基因仅在确定性内胚层中表达，但确定性内胚层通过表达 FOXA2、SOX17、GATA4、GATA6、CXCR4、GSC 和 E-cadherin（CDH1）等基因的组合来表征（源自 Yasunaga et al. 2005 的鼠同源物推断）。CDH1 是上皮细胞的通用标记物，CXCR4 是化学趋化受体，常与 CDH1 一起作为确定性内胚层的表面标记物（源自 Yasunaga et al. 2005 的鼠同源物推断）。
英文描述
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits.
The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors.
Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene.
cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane.
The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors.
Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene.
cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane.
所含基因
44 个基因