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

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.

Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

“…This requires major changes in chromatin organization and (super) enhancer activity and is thought to be regulated by the Trp63 -mediated induction of the SWI/SNF chromatin remodeling factor Smarca4 (previously called Brg1 ) (Mardaryev et al, 2014), while also possibly involving GRHL3 (Klein et al, 2017; Poterlowicz et al, 2017). Recent work suggests that reduced tension of the nuclear lamina in suprabasal keratinocytes, resulting from the loss of ITGB1 attachment to the extracellular matrix, can also directly induce physical relocation and transcriptional activation of the EDC locus (Carley et al, 2021). Interestingly, we also observe changes in nuclear shape and size in response to hyperactive WNT/CTNNB1 signaling (Supplementary Figure 2).…”

Culturing Keratinocytes on Biomimetic Substrates Facilitates Improved Epidermal Assembly In Vitro

“…Similarly, β1 integrin-dependent tension is exerted on the LINC complex, which represses epidermal differentiation in mouse keratinocytes. As a consequence, loss of both Sun1 and Sun2 in mice increases epidermal thickness [ 9 ].…”

“…Engagement of integrins at the epidermal basement membrane relays high tension to the nucleus via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex; reportedly resulting in repression of differentiation and maintenance of keratinocyte progenitor cells [ 9 ]. The LINC complex is comprised of the evolutionarily conserved nesprin and the Sun-domain proteins that span the nuclear envelope.…”

“…This transition from a proliferative to a differentiated phenotype has been attributed to the degree of tension placed on the nuclear lamina, particularly lamin A. In keratinocytes with high levels of integrin-mediated adhesion, the tension on lamin A is high, but migration away from the basement membrane results in the loss of these focal adhesions and relaxation of lamin A tension [ 9 ]. The role of lamins in epidermal differentiation is further consolidated by a study on a skin-specific triple lamin knockout mouse model ( Lmna−/− Lmnb1Δ/Δ Lmnb2Δ/Δ ), which exhibit precocious epidermal differentiation, evidenced by thickening of the epidermis and hyperkeratosis [ 21 ].…”

Tissue scale properties of the extracellular matrix regulates nuclear shape, organisation and fate in the embryonic midline sutures

“…9 59 60 46 61 47 62 63. While the LINC complex comprises several proteins, including Nesprins (Syne1, Syne2), Sun (Sun1, Sun2), Lamin (Lmna, Lmnb1) proteins mediate LINC mediated mechanoresponse by modulating chromatin dynamics and tissue-specific gene expression11 39 55 56 57 58 59 38. LMNA also modulates its own transcription where Lmna expression and envelope localisation is directly correlated with tissue stiffness, and stiff substrates drive increased Lmna expression when MSCs are grown on skeletogenic stiff substrates 8 41 11 46 64 26 9 39 41.…”