Mechanochemical control of epidermal stem cell divisions by B-plexins

Abstract

The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data uncover a central role of Bplexins in mechanosensation to couple cell density and cell division in development and disease.

The Hippo pathway mediates Semaphorin signaling

“…For example, laminar and oscillatory shear can regulate PLXND1 configuration to influence cellular mechanoresponses during atherosclerosis. During development, cell-cell contact may also act through PLXNB to control YAP/TAZ subcellular location, but the exact effects of plexins on YAP activity are not entirely consistent among different studies (39)(40)(41). We observed that overexpression of PLXNA1 or PLXND1 did not counteract YAP phosphorylation by high cell density, whereas expression of the positive control lysophosphatidic acid receptor LPAR1 decreased YAP phosphorylation (Fig.…”

“…Mechanical cues-such as cell-cell contact, matrix stiffness, and flow shear-can regulate Hippo signaling (11,38). PLXND1 and PLXNB1/2 were reported to respond to mechanical cues to modulate cell behaviors (39)(40)(41). For example, laminar and oscillatory shear can regulate PLXND1 configuration to influence cellular mechanoresponses during atherosclerosis.…”

The Hippo signalling pathway and its implications in human health and diseases

“…96,98 In summary, different mechanical cues are involved in the upstream regulation of the Hippo pathway. Although it has been found that integrin, 99 peizo 100 and plexin 101 can act as mechanical sensor proteins that transmit signals to the Hippo pathway, the comprehensive molecular mechanism by which cells sense mechanical signals and change cellular behaviours through the Hippo pathway is still unclear. The proteins in cellcell contact sites and the cytoskeleton might play critical roles in the signal transmission between mechanical cues and the Hippo pathway cascade.…”

Biomechanical property of limbal niche maintains stemness through YAP

“…1H-J). To further exclude the possibility of non-specific reagent activity, knockdown was performed with 2 conventional previously validated silencing RNAs against YAP (siYAP) (Dupont et al , 2011) or with the pharmacological inhibitor of YAP, Verteporfin (Ning et al , 2021; McGinn et al , 2021; Jiang et al , 2021). In agreement, both siRNA repression (S1A-B) and pharmacology inhibition (Fig.…”