Integrating mechanical signals into cellular identity.

The large arrays of cell types in a multicellular organism are defined by their stereotypic size and/or morphology, and, for cells in vivo, by their anatomic positions. Historically, this identity-structure-function correlation was conceptualized as arising from distinct gene expression programs that dictate how cells appear and behave. However, a growing number of studies suggest that a cell's mechanical state is also an important determinant of its identity, both in lineage-committed cells and in pluripotent stem cells. Defining the mechanism by which mechanical inputs influence complex cellular programs remains an area of ongoing investigation. Here, we discuss how the cytoskeleton actively participates in instructing the response of the nucleus and genome to integrate mechanical and biochemical inputs, with a primary focus on the role of the actomyosin-LINC (linker of nucleoskeleton and cytoskeleton) complex axis.

The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation.

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.