Abstract
While the mechanisms by which chemical signals control cell fate have been well studied, the impact of mechanical inputs on cell fate decisions is not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through linker of nucleoskeleton and cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.
Highlights
Physical forces and the architecture of the extracellular environment are an emerging area of cell fate regulation (Discher et al, 2009)
We inserted a tension sensor module composed of the fluorescence resonance energy transfer (FRET) pair mTFP and Venus connected by an elastic flagelliform linker (Grashoff et al, 2010) into the juxtamembrane region of a miniNesprin-2 construct (Luxton et al, 2011), called hereafter ‘N2G-JM-TSMod’
We demonstrate that linker of nucleoskeleton and cytoskeleton (LINC) complex tension in mouse keratinocytes (MKCs) responds to b1 integrin engagement in a cell-intrinsic manner
Summary
Physical forces and the architecture of the extracellular environment are an emerging area of cell fate regulation (Discher et al, 2009). While several studies have linked geometrical and physical inputs to changes in cellular signaling through mechanoresponsive transcription factors such as YAP/ TAZ (Totaro et al, 2018) or MKL/MRTF (Connelly et al, 2010), whether direct transmission of mechanical force to the nucleus can influence cell fate is not known. We explore whether mechanical cues can regulate keratinocyte cell fate via tension on the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. The AP-1 transcription factor complex, itself regulated by A-type lamins, influences EDC gene expression in both proliferating and differentiating keratinocytes in vitro (Oh et al, 2014). This work suggests that tension from integrins is communicated through the LINC complex to the nuclear lamina to maintain the progenitor state of basal keratinocytes, providing a potential mechanism by which cell fate is regulated directly by mechanical cues
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