Rho GTPases Mediate the Mechanosensitive Lineage Commitment of Neural Stem Cells§

Authors

  • Albert J. Keung,

    1. Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California, USA
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  • Elena M. de Juan-Pardo,

    1. Department of Bioengineering, University of California, Berkeley, California, USA
    2. CEIT and Tecnun, University of Navarra, Manuel de Lardizábal 15, 20018 San Sebastián, Spain
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  • David V. Schaffer,

    Corresponding author
    1. Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California, USA
    2. Department of Bioengineering, University of California, Berkeley, California, USA
    3. Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA
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    • Telephone: 510-643-5963; Fax: 510-642-4778

  • Sanjay Kumar

    Corresponding author
    1. Department of Bioengineering, University of California, Berkeley, California, USA
    • 274A Stanley Hall, University of California at Berkeley, Berkeley, CA 94720-3220, USA
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    • Telephone: 510-643-0787; Fax: 510-642-5835


  • Author contributions: A.J.K.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; E.d.J.-P.: conception and design, collection and/or assembly of data, and data analysis and interpretation; D.V.S. and S.K.: financial support, conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript. A.J.K. and E.d.J.-P. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS September 28, 2011.

Abstract

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. STEM CELLS 2011;29:1886–1897

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