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The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation
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The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation
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Paper
The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation
2020
Overview
Abstract While the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are 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. Competing Interest Statement The authors have declared no competing interest. Footnotes * This revised manuscript includes three major additions: 1) further characterization of the N2G-JM-TSMod LINC complex tension sensor (Fig. 1); 2) ATAC-seq analysis demonstrating precocious accessibility of epidermal differentiation genes in the absence of LINC complexes (Fig. 5) and 3) use of mouse keratinocytes lacking beta-1 integrin to probe the requirement for cell-ECM engagement to both drive high tension on the LINC complex (Fig. 1) and to repress epidermal differentiation (Fig. 4). Supplementary files for bioinformatic analysis and the links to the raw sequencing data are also provided. * https://www.ncbi.nlm.nih.gov/bioproject/PRJNA636991
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
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