Apico-basal cell compression regulates Lamin A/C levels in epithelial tissues

Abstract

The levels of nuclear protein Lamin A/C are crucial for nuclear mechanotransduction. Lamin A/C levels are known to scale with tissue stiffness and extracellular matrix levels in mesenchymal tissues. But in epithelial tissues, where cells lack a strong interaction with the extracellular matrix, it is unclear how Lamin A/C is regulated. Here, we show in epithelial tissues that Lamin A/C levels scale with apico-basal cell compression, independent of tissue stiffness. Using genetic perturbations in Drosophila epithelial tissues, we show that apico-basal cell compression regulates the levels of Lamin A/C by deforming the nucleus. Further, in mammalian epithelial cells, we show that nuclear deformation regulates Lamin A/C levels by modulating the levels of phosphorylation of Lamin A/C at Serine 22, a target for Lamin A/C degradation. Taken together, our results reveal a mechanism of Lamin A/C regulation which could provide key insights for understanding nuclear mechanotransduction in epithelial tissues.

The laminin-keratin link shields the nucleus from mechanical deformation and signalling

“…Apart from nuclear YAP translocation, forces applied to the nucleus can trigger different mechanotransduction events, which could also take place in our system. For instance, Lamin A/C levels have been shown to affect nuclear mechanics and nuclear shape integrity 72,73 , and nuclear deformation regulates Lamin A/C levels 74 . We found no significant difference between WT and β4R1281W cells in the overall expression levels of lamin A/C, indicating that the nuclear lamina was not compromised (Supplementary Fig.…”

A single-molecule localization microscopy method for tissues reveals nonrandom nuclear pore distribution in Drosophila

“…In mammals, the levels of Lamin A/C rise with increasing tissue stiffness and these form a meshwork in the nuclear lamina distinct from that formed by Lamin B filaments that increases the stiffness of the nuclear envelope, thereby protecting it from mechanical deformation (Lammerding et al, 2006;Swift et al, 2013). It has recently been found that Lamin C expression in Drosophila epithelia shows a similar correlation with apical compression (Iyer et al, 2021). Both the peripodial membrane and the folds of the wing disc are under compression and have high Lamin C levels, whereas the wing pouch epithelium, which is not compressed, has low levels.…”

Nucleus size and its effect on the chromatin structure in living cells

“…Namely, from the results published in ref. [25,117], it follows that the cell shape and/or mechanical properties of the surround-ing environment have a profound effect on the expression level of lamin A, which, in turn, has a strong influence on the elastic properties of the nuclear lamina network and therefore the surface tension of the NE [47]. The latter, according to our study, determines the nucleus size and, as a result, nucleosome stability, which may have a global impact on gene transcription profiles.…”

“…Specifically, based on recent experimental studies it has been suggested that by modulating DNA-binding properties of architectural proteins, cells may be able to actively respond to a wide range of environmental cues via changing the condensation level of various parts of DNA and switching between different gene expression patterns [12][13][14][15][16][17][18]. Furthermore, it has been found that such a mechanism not only plays the central role in cell response to chemical signals [12][13][14], but also to extracellular mechanical forces as well [16][17][18][19][20][21][22][23][24][25]. In the latter case, rearrangement of the chromatin structure and changes in gene transcription have been found to be tightly associated with alternations in the nucleus size and shape [18,21,25].…”

“…Furthermore, it has been found that such a mechanism not only plays the central role in cell response to chemical signals [12][13][14], but also to extracellular mechanical forces as well [16][17][18][19][20][21][22][23][24][25]. In the latter case, rearrangement of the chromatin structure and changes in gene transcription have been found to be tightly associated with alternations in the nucleus size and shape [18,21,25]. Yet, despite a profound role of mechanical forces in regulation of the nuclear organization, the exact molecular mechanisms underlying it still remain unclear.…”