ECM-dependent HIF induction directs trophoblast stem cell fate via LIMK1-mediated cytoskeletal rearrangement.
ECM-dependent HIF induction directs trophoblast stem cell fate via LIMK1-mediated cytoskeletal rearrangement.
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DOI：
10.1371/journal.pone.0056949
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Maltepe E
中科院分区：
文献类型：
--
作者：
Choi HJ;Sanders TA;Tormos KV;Ameri K;Tsai JD;Park AM;Gonzalez J;Rajah AM;Liu X;Quinonez DM;Rinaudo PF;Maltepe E
缺氧诱导因子 (HIF) 转录调节因子家族协调数十个基因的表达以响应缺氧。哺乳动物的发育发生在缺氧环境中，因此 HIF 缺失小鼠会因多种胚胎和胎盘缺陷而在子宫内死亡。小鼠胚胎干细胞不分化为胎盘细胞；因此，滋养层干细胞 (TSC) 用于研究小鼠胎盘发育。与子宫内胎盘发育过程中对 HIF 活性的要求一致，源自 HIF 缺失小鼠的 TSC 表现出严重的分化缺陷，并且无法在体外形成滋养层巨细胞 (TGC)。有趣的是，分化的 TSC 通过尚不清楚的机制诱导独立于氧张力的 HIF 活性。在这里，我们发现改变 TSC 培养的细胞外基质 (ECM) 组成会改变它们从 TGC 向多核合体滋养体 (SynT) 的分化潜力，并阻断不依赖于氧的 HIF 诱导。我们进一步发现 ECM 组合物对有丝分裂原激活蛋白激酶激酶-1/2 (MAP2K1/2、MEK-1/2) 信号传导的调节是造成这种效应的原因。在缺乏 ECM 依赖性信号的情况下，缺氧信号通路会激活该 MAPK 级联，以驱动 HIF 诱导并沿着 TGC 谱系重定向 TSC 的命运。此外，我们发现微管和肌动蛋白细胞骨架的完整性对于 TGC 命运的决定至关重要。 HIF-2α 通过与 c-MYC 相互作用诱导 Lim 结构域激酶 1（一种调节微管和肌动蛋白稳定性以及细胞侵袭的酶）的非规范表达，确保 TSC 细胞骨架完整性并促进侵袭性 TGC 形成。因此，我们发现 HIF 可以整合 TSC 生态位内的位置和代谢线索，通过非规范基因表达调节细胞骨架来调节胎盘发育。
The Hypoxia-inducible Factor (HIF) family of transcriptional regulators coordinates the expression of dozens of genes in response to oxygen deprivation. Mammalian development occurs in a hypoxic environment and HIF-null mice therefore die in utero due to multiple embryonic and placental defects. Mouse embryonic stem cells do not differentiate into placental cells; therefore, trophoblast stem cells (TSCs) are used to study mouse placental development. Consistent with a requirement for HIF activity during placental development in utero, TSCs derived from HIF-null mice exhibit severe differentiation defects and fail to form trophoblast giant cells (TGCs) in vitro. Interestingly, differentiating TSCs induce HIF activity independent of oxygen tension via unclear mechanisms. Here, we show that altering the extracellular matrix (ECM) composition upon which TSCs are cultured changes their differentiation potential from TGCs to multinucleated syncytiotropholasts (SynTs) and blocks oxygen-independent HIF induction. We further find that modulation of Mitogen Activated Protein Kinase Kinase-1/2 (MAP2K1/2, MEK-1/2) signaling by ECM composition is responsible for this effect. In the absence of ECM-dependent cues, hypoxia-signaling pathways activate this MAPK cascade to drive HIF induction and redirect TSC fate along the TGC lineage. In addition, we show that integrity of the microtubule and actin cytoskeleton is critical for TGC fate determination. HIF-2α ensures TSC cytoskeletal integrity and promotes invasive TGC formation by interacting with c-MYC to induce non-canonical expression of Lim domain kinase 1–an enzyme that regulates microtubule and actin stability, as well as cell invasion. Thus, we find that HIF can integrate positional and metabolic cues from within the TSC niche to regulate placental development by modulating the cellular cytoskeleton via non-canonical gene expression.
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影响因子：
3.4
作者：
Hughes, Chris S.;Radan, Lida;Lajoie, Gilles A.
通讯作者：
Lajoie, Gilles A.
影响因子：
9.2
作者：
Giroux, S;Tremblay, M;Charron, J
通讯作者：
Charron, J
影响因子：
4.8
作者：
Asanoma, Kazuo;Kato, Hidenori;Wake, Norio
通讯作者：
Wake, Norio
DOI：
10.1073/pnas.0507399103
发表时间：
2006-01-31
影响因子：
11.1
作者：
Galabova-Kovacs, G;Matzen, D;Baccarini, M
通讯作者：
Baccarini, M
影响因子：
5.3
作者：
Emerling, BM;Platanias, LC;Chandel, NS
通讯作者：
Chandel, NS