Phosphoinositide 3-kinase alpha-dependent regulation of branching morphogenesis in murine embryonic lung: evidence for a role in determining morphogenic properties of FGF7.
Phosphoinositide 3-kinase alpha-dependent regulation of branching morphogenesis in murine embryonic lung: evidence for a role in determining morphogenic properties of FGF7.
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DOI：
10.1371/journal.pone.0113555
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ward SG
中科院分区：
文献类型：
--
作者：
Carter E;Miron-Buchacra G;Goldoni S;Danahay H;Westwick J;Watson ML;Tosh D;Ward SG
分支形态发生是许多上皮器官发育的关键步骤。磷脂酰肌醇-3-激酶（PI 3 K）途径已被确定为这一过程的核心组成部分，但确切的作用尚未完全确定。在此，我们试图使用一系列针对该途径的药理学抑制剂来确定PI 3 K在小鼠肺分支中的作用。泛I类PI 3 K抑制剂ZSTK 474极大地增强了全鼠肺外植体的分支潜力，如通过与对照相比在48小时内末端分支数目的增加所测量的。在抑制PI 3 K、Akt和mTOR的下游信号传导组分后也观察到这种分支的增强。PI 3 K的同种型选择性抑制剂确定PI 3 K的α同种型是分支形态发生中的关键驱动因素。为了确定PI 3 K抑制对分支的影响是对肺上皮特异性的还是继发于对间充质的影响，我们评估了PI 3 K抑制在无间充质肺上皮培养物中的影响。与FGF 7培养的分离的肺上皮形成大的囊样结构，而与FGF 7和ZSTK 474共培养诱导形成具有完整管腔的限定分支。总之，这些数据表明PI 3 K在小鼠胚胎肺的分支程序中的新作用与在其他分支器官中报道的相反。我们的观察还指出PI 3 K作为FGF 7信号传导的形态发生开关。
Branching morphogenesis is a critical step in the development of many epithelial organs. The phosphoinositide-3-kinase (PI3K) pathway has been identified as a central component of this process but the precise role has not been fully established. Herein we sought to determine the role of PI3K in murine lung branching using a series of pharmacological inhibitors directed at this pathway. The pan-class I PI3K inhibitor ZSTK474 greatly enhanced the branching potential of whole murine lung explants as measured by an increase in the number of terminal branches compared with controls over 48 hours. This enhancement of branching was also observed following inhibition of the downstream signalling components of PI3K, Akt and mTOR. Isoform selective inhibitors of PI3K identified that the alpha isoform of PI3K is a key driver in branching morphogenesis. To determine if the effect of PI3K inhibition on branching was specific to the lung epithelium or secondary to an effect on the mesenchyme we assessed the impact of PI3K inhibition in cultures of mesenchyme-free lung epithelium. Isolated lung epithelium cultured with FGF7 formed large cyst-like structures, whereas co-culture with FGF7 and ZSTK474 induced the formation of defined branches with an intact lumen. Together these data suggest a novel role for PI3K in the branching program of the murine embryonic lung contradictory to that reported in other branching organs. Our observations also point towards PI3K acting as a morphogenic switch for FGF7 signalling.
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影响因子：
4.6
作者：
Rawlins, Emma L.;Clark, Cheryl P.;Hogan, Brigid L. M.
通讯作者：
Hogan, Brigid L. M.
影响因子：
2.7
作者：
Larsen, M;Hoffman, MP;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
5.7
作者：
Kong, Dexin;Yamori, Takao
通讯作者：
Yamori, Takao
DOI：
10.3410/b2-78
发表时间：
2010-11-11
期刊：
F1000 biology reports
影响因子：
--
作者：
Hinz B;Gabbiani G
通讯作者：
Gabbiani G
DOI：
10.1042/bj20110502
发表时间：
2011-08-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Jamieson S;Flanagan JU;Kolekar S;Buchanan C;Kendall JD;Lee WJ;Rewcastle GW;Denny WA;Singh R;Dickson J;Baguley BC;Shepherd PR
通讯作者：
Shepherd PR