Rho GTPases mediate the mechanosensitive lineage commitment of neural stem cells.
Rho GTPases mediate the mechanosensitive lineage commitment of neural stem cells.
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DOI：
10.1002/stem.746
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Keung AJ;de Juan-Pardo EM;Schaffer DV;Kumar S
成体神经干细胞(NSCs)在学习和记忆中发挥着重要作用，并受到神经系统疾病的负面影响。众所周知，生化和遗传因素调节自我更新和分化，最近有研究表明，机械和固态信号，如细胞外基质(ECM)硬度，也可以调节神经干细胞和其他类型干细胞的功能。然而，对于干细胞将机械输入转化为命运决定的分子机制、机械输入在多大程度上指导命运决定与选择或反对血统承诺的原始细胞群体，或者在天然干细胞利基中机械转导信号分子的体内相关性，我们知之甚少。在这里，我们证明了ECM来源的机械信号通过Rho GTP酶在分化的关键早期窗口激活细胞收缩机制，从而调节NSC的谱系承诺。此外，在越来越硬的ECM上培养神经干细胞可以增强RhoA和CDC42的激活，增加NSC的硬度，并抑制神经发生。同样，抑制RhoA和CDC42或细胞收缩的下游调节因子可以将神经干细胞从僵硬的基质和Rho GTP酶诱导的神经抑制中拯救出来。重要的是，Rho GTPase的表达和ECM硬度不会改变增殖或凋亡率，这表明一种指导性的而不是选择性的机制调节了谱系分布。最后，在成人大脑中，海马体前体细胞中的RhoA激活抑制神经发生，类似于它在体外的作用。这些结果确立了基于Rho GTPase的机械转导和细胞硬度是体外NSC命运的生物物理调节因子，而RhoA是海马干细胞巢中重要的调节蛋白。
Adult neural stem cells (NSCs) play important roles in learning and memory and are negatively impacted by neurological disease. It is known that biochemical and genetic factors regulate self-renewal and differentiation, and it has recently been suggested that mechanical and solid-state cues, such as extracellular-matrix (ECM) stiffness, can also regulate the functions of NSCs and other stem cell types. However, relatively little is known of the molecular mechanisms through which stem cells transduce mechanical inputs into fate decisions, the extent to which mechanical inputs instruct fate decisions versus select for or against lineage-committed blast populations, or the in vivo relevance of mechanotransductive signaling molecules in native stem cell niches. Here we demonstrate that ECM-derived mechanical signals act through Rho GTPases to activate the cellular contractility machinery in a key early window during differentiation to regulate NSC lineage commitment. Furthermore, culturing NSCs on increasingly stiff ECMs enhances RhoA and Cdc42 activation, increases NSC stiffness, and suppresses neurogenesis. Likewise, inhibiting RhoA and Cdc42 or downstream regulators of cellular contractility rescues NSCs from stiff matrix- and Rho GTPase-induced neurosuppression. Importantly, Rho GTPase expression and ECM stiffness do not alter proliferation or apoptosis rates indicating that an instructive rather than selective mechanism modulates lineage distributions. Finally, in the adult brain, RhoA activation in hippocampal progenitors suppresses neurogenesis, analogous to its effect in vitro. These results establish Rho GTPase-based mechanotransduction and cellular stiffness as biophysical regulators of NSC fate in vitro and RhoA as an important regulatory protein in the hippocampal stem cell niche.
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影响因子：
4.8
作者：
Endo, Makoto;Antonyak, Marc A.;Cerione, Richard A.
通讯作者：
Cerione, Richard A.
DOI：
10.1083/jcb.200308101
发表时间：
2004-01-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hsieh J;Aimone JB;Kaspar BK;Kuwabara T;Nakashima K;Gage FH
通讯作者：
Gage FH
影响因子：
1.9
作者：
Huentelman, Matthew J.;Stephan, Dietrich A.;Talboom, Joshua;Corneveaux, Jason J.;Reiman, David A.;Gerber, Jill D.;Barnes, Carol A.;Alexander, Gene E.;Reiman, Eric M.;Bimonte-Nelson, Heather A.
通讯作者：
Bimonte-Nelson, Heather A.
影响因子：
8.2
作者：
Balu, Darrick T.;Lucki, Irwin
通讯作者：
Lucki, Irwin
影响因子：
14
作者：
Banerjee, Akhilesh;Arha, Manish;Choudhary, Soumitra;Ashton, Randolph S.;Bhatia, Surita R.;Schaffer, David V.;Kane, Ravi S.
通讯作者：
Kane, Ravi S.