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

Emma Carley*, Rachel M. Stewart*, Abigail Zieman*, Amanda Zubek, Samantha Lin, Valerie Horsley*, Megan C. King*

Preprint posted on 4 May 2020 https://www.biorxiv.org/content/10.1101/2020.05.03.075085v1

Article now published in eLife at http://dx.doi.org/10.7554/eLife.58541

Nuclei under tension: pushing down on epithelial differentiation

Selected by Helena Pinheiro

Background:

The regulation of cell fate has been a matter of great interest for a long time. Chemical cues are important to determine cell fate, however, advances in the field showed that mechanical stimuli also play a determinant role (Discher, 2009).

The epithelial tissue is a great model to study the influence of mechanical forces in differentiation since cell adhesions change during this process. At the base of the epithelial tissue, stem cells interact with the basal membrane through integrin-based adhesions. Upon differentiation, the cells lose the adhesion to the basal membrane and move upwards across the stratified epithelium, establishing E-cadherin-based cell-to-cell contacts until the keratinocytes are shed at the surface of the skin.

Previous observations led to the idea that the nuclear lamina is implicated in this process. In fact, a thickening of the epidermis was described in a mouse with skin-specific depletion of nuclear lamins, consistent with precocious differentiation (Jung et al., 2014). However, it is unknown how the mechanical cues from the extracellular environment are propagated to the nucleus. In this study, the authors explore the possibility that the forces from the adhesions are transmitted via the LINC complex and exert an effect on differentiation. The LINC complex serves as a link between the cytoskeleton and the nuclear lamina, through the interaction of SUN proteins at the nuclear envelope and nesprin proteins that interact with the cytoskeleton.

 

Key findings:

In this preprint the authors used a mini-nesprin construct with a tension sensor module that allows the measurement of tension exerted on the LINC complex. By plating undifferentiated primary keratinocytes in different substrates, the authors observed a higher tension exerted on the LINC complex when cells were plated in fibronectin, which engages integrin adhesions. The tension was decreased in cells treated with latrunculin, indicating that these forces depend on filamentous actin.

Culturing primary keratinocytes with high calcium leads to the formation of cohesive colonies that mimic the extracellular integrin-based adhesions in the periphery of the colonies and the cadherin-based cell-cell adhesions in the center. The authors took advantage of this nice in vitro system and observed that the LINC complex is under higher tension in undifferentiated cells in the edge of the colonies. Using conformational sensitive lamin antibodies, they observed that this tension was transmitted to the nuclear lamina. Coincident with a role in differentiation, the cells in the center of the colonies, in which the nucleus is under less tension, express epithelial differentiation markers.

To study how LINC complexes could affect differentiation in vivo, the authors used a Sun1/Sun2 knockout mouse, in which the LINC complex is abolished. They observed that these mice have a thickened epidermis, concordant with precocious differentiation of the epidermal tissue. This effect was not due to increased cell proliferation and the interactions at the basal lamina were similar to wild-type mice. Interestingly, they observed that the keratinocytes regenerate faster in the epithelial tissue of Sun KO skin. Thus, the differentiation process is occurring at a faster rate in Sun KO epithelium as progenitor cells detach from the basal membrane more rapidly without LINC complexes. This strongly suggests that the LINC complex is important to regulate epithelial differentiation in vivo. Accordingly, culturing Sun KO keratinocytes in vitro showed that these cells have a transcriptional profile consistent with precocious differentiation. While there is a distinction between the transcription of differentiation markers in the edge of wild type cultures comparing with the center, Sun KO cells lose this positional input to differentiation.

These observations indicate that the tension exerted on the LINC complex, mediated by integrin-based interactions at the basal membrane, acts as a repressor of epithelial differentiation by regulating epidermal stem cells’ transcriptional profile.

 

The regulation of cellular and biological processes by mechanical forces is a subject that particularly fascinates me. I especially enjoyed the elegant way the authors demonstrate it in this preprint. The work builds up consistently going through this mechanism both in vitro and in vivo, taking advantage of an excellent model to study cell fate mechanical regulation.

 

Question for the authors:

In your previous work, you observed the formation of a perinuclear cage after differentiation induction (Stewart et al, 2015). Do you envision that the perinuclear cage can act as a nucleus “shield” and contribute to the decrease in forces applied in the nuclear envelope during differentiation?

 

References:

Discher, D.E., D.J. Mooney, and P.W. Zandstra. 2009. Growth factors, matrices, and forces combine and control stem cells. Science. 324:1673-7.10.1126/science.1171643

Jung, H.J., A. Tatar, Y. Tu, C. Nobumori, S.H. Yang, C.N. Goulbourne, H. Herrmann, L.G. Fong, and S.G. Young. 2014. An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin. Mol Cell Biol. 34:4534-44.10.1128/mcb.00997-14

Stewart, R.M., A.E. Zubek, K.A. Rosowski, S.M. Schreiner, V. Horsley, and M.C. King. 2015. Nuclear-cytoskeletal linkages facilitate cross talk between the nucleus and intercellular adhesions. J Cell Biol. 209:403-18.10.1083/jcb.201502024

 

Tags: mechanobiology, mechanotransduction

Posted on: 12 May 2020

doi: https://doi.org/10.1242/prelights.20526

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Author's response

Megan C. King and Valerie Horsley shared

Our prior work did indicate that keratinocytes organize their cytoskeleton—actin, microtubules, and keratins—as perinuclear cages around the nucleus during differentiation.  Interestingly, tension on the nuclear lamina could trigger the formation of the perinuclear actin cage, as suggested by work from Sara Wickstrom’s lab when investigating stretch on keratinocyte monolayers (Le et al., Nat Cell Bio, 2016). Given that the skin is constantly mechanically challenged, the perinuclear cytoskeletal may broadly act to mechanically protect the nucleus, as suggested. However, it is important to note that the cytoskeleton is dynamic and linked to the continual remodeling of cellular adhesions (adherens junctions and tight junctions) to maintain barrier homeostasis during constant cell turnover. In the future, it will be interesting to probe how the mechanotransduction pathways and nuclear protection pathways are integrated during the multiple stages of cellular differentiation in the epidermis and other tissues.

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