# Mechanics of force transmission in epithelia: From cell-to-cell propagation to nuclear response

Ronan Bouzignac, Magali Suzanne

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Ronan Bouzignac, Magali Suzanne. Mechanics of force transmission in epithelia: From cell-to-cell propagation to nuclear response. Seminars in Cell and Developmental Biology, 2025, 175, pp.103662. 10.1016/j.semcdb.2025.103662. hal-05534516

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Review

# Mechanics of force transmission in epithelia: From cell-to-cell propagation to nuclear response

Ronan Bouzignac, Magali Suzanne*

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University of Toulouse, CNRS, Molecular, Cellular and Developmental Biology Unit (MCD), Centre de Biologie Intégrative (CBI), Toulouse, France

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## ARTICLE INFO

Keywords:

Mechanical forces
Propagation
Nuclear envelope
Nuclear rupture
Nuclear collapse
Morphogenesis

## ABSTRACT

Mechanical forces play essential roles during morphogenesis, enabling cells to change shape or reorganize to form new structures. Recent questions in the field of mechanobiology focus on how these locally generated forces propagate and the extent of their propagation. This phenomenon can be observed at multiple scales (across tissues, where supracellular actomyosin structures interconnected at cell-cell junctions transmit forces, or within individual cells, where mechanical cues can influence the nucleus). In the first part of this review, we highlight recent advances in our understanding of force propagation along epithelial apical surfaces, including factors that facilitate it, such as tissue curvature and polarity. In the second part, we examine how mechanical forces affect nuclear shape and integrity at the single-cell level, beginning with *in vitro* studies of nuclear responses to mechanical stress and extending to the less-explored mechanical behavior of nuclei in more complex, integrated model systems.

## 1. Introduction

The importance of physical aspects in biology is now well admitted and constitutes a growing field of research. Cells are not only submitted to external forces and constraint, they are also generating forces in order to change their shape, divide, dye or migrate. Here, we first summarize and discuss recent advances in the field on force propagation in epithelial tissues. Although some recent works offer new perspectives into how forces are integrated at a multiscale level, with the description of an interconnected basal actomyosin network to basal spot junctions in *Drosophila* embryo [45] or the interconnection of basal actomyosin pulses in the ovary [50], we chose to focus here on force propagation along the apical surface of the epithelium that has been more extensively described. Then, in a second part, we describe what we know about how forces propagate at a single cell level and how it impacts the nucleus, starting with a description of nuclear physical properties, then describing how nuclei respond to physical challenges, from nuclear deformation to rupture and collapse.

## 2. Force propagation across tissues

The first part of this review mainly focuses on a few examples where the mechanistic of force propagation is now better understood. We

describe how forces, originating from a small number of contracting cells, propagate in a whole domain creating a wave of contractility, highlighting how tissue shape or polarity could influence the efficiency of force propagation. We then discuss recent discoveries offering new perspectives in the integration of forces in 3D at a multiscale level.

### 2.1. Planar forces transmission

#### 2.1.1. From individual cell contractility to the coordination of a whole territory

Planar force transmission has been particularly well studied during *Drosophila* mesoderm invagination. In this model system, the cellular mechanism of apical constriction was initially described as a rachet-like mechanism, relying on pulsed contraction of a subapical actomyosin meshwork [57]. Interestingly, this apical constriction is not synchronous in the whole mesoderm territory and proceeds in two phases. The first Snail-dependent stochastic wave corresponds to uncoordinated and unstable constrictions, during which the tissue shape does not change. It is followed by a second Twist-dependent wave of coordinated and stabilized constrictions, where a large number of cells reduce their apex leading to the initiation of furrow formation [42]. The coordination of this second wave relies on the tight connection established between mesodermal cells [56], leading to the propagation of the constriction

<footnote>* Corresponding author.
E-mail address: magali.suzanne@univ-tlse3.fr (M. Suzanne).</footnote>
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Force propagation during morphogenesis: from planar transmission to 3D propagation. A. During the mesoderm invagination in *Drosophila* embryo, individual cells are first constricting apically, then apico-basally. Both forces propagate planarly in the neighboring tissue favoring the coordination of the invagination. B. During endoderm invagination in *Drosophila* embryo, apical constriction initiates in specific regions and propagates directionally, driven by tissue flow and influenced by the curvature and resistance provided by the vitelline envelope, resulting in a polarized wave of MyoII. C-D In both *Drosophila* leg imaginal disc and chicken neural tube bending, apical constriction then apico-basal traction induces localized deformation of the apical surface in the cells and their nearest neighbors. Due to the polarization of the tissue, this mechanical signal propagates preferentially in one direction and triggers the folding process. D. In *Drosophila* embryo, myosin contraction propagates along the membrane in all direction. During cephalic furrow formation in *Drosophila* embryo, planar polarized MyoII ribbons align along the lateral membranes, correcting genetic noise and ensuring a precise and stereotyped invagination.</figcaption></figure>

wave to the whole mesodermal territory (Fig. 1A). The idea of a me-
chanical signal initiated by a subset of contracting cells is first supported
by the rescue of *snail* mutant by a local indentation of the ventral part of
the embryo [74], together with biophysical simulations [19]. However,
it is only recently that the propagation of the constriction wave was
tested experimentally by an elegant methods using magnetic nano-
particles injected in the ventral part of the embryo and stimulated by a
small magnet [63]. Using this method, the authors mimic physiological
pulses generated during the first constriction wave, and show that this is
sufficient to rescue MyoII apical accumulation in the mesoderm tissue
and invagination. They further do local indentation and could visualize
the propagation of MyoII apical recruitment in the neighboring territory.

Thus, in this model, a first stochastic constriction wave is generating
a mechanical signal ensuring the propagation of constriction through
the Folded gastrulation (Fog) signaling pathway [55], including the
activation of a G-protein coupled receptor (GPCR) and finally triggering
the activation of actomyosin. This leads to the coordinated constriction

of the whole mesodermal territory and finally initiating the invagina-
tion. This propagation wave relies on the formation of a supracellular
actomyosin network structurally redundant ensuring morphogenesis
robustness [93].

Finally, this planar transmission of forces is followed by an increase
in apico-basal contractility [29,39], which appears to play a key func-
tion in the invagination process [29].

2.1.2. *The role of tissue curvature in force propagation*

Planar force propagation can also be strongly influenced by the
shape of the tissue, as shown in *Drosophila* endoderm invagination. This
invagination relies on the local expression of the GPCR ligand Fog in a
few rows of cells, that activates autonomously the Rho1/Rok/MyoII
pathway leading to apical constriction in this domain. Then a propa-
gation wave is generated through a mechanical feedback loop inducing
the activation of MyoII in the neighboring anterior cells [5]. Indeed, the
inhibition of MyoII during the propagation blocks the wave of Rho1
activation, supporting the fact that this propagation wave is driven
mechanically. However, in this model, MyoII propagation wave appears
independent of Fog (with no impact of Fog overexpression on MyoII
dynamics). Finally, in this model, two other factors influence the me-
chanical propagation of apical constriction. First, local adhesion of the
epithelium to the vitelline membrane through the aPS3 integrin *scab*,
occurs prior to the invagination, creates a mechanical resistance to
anterior movement and thus contributes to the propagation of MyoII
wave [5,14]. Second, the mismatch between the initial localization of
apical Myosin recruitment and the maximum curvature of the embryo
contributes to the creation of tissue flow and to the polarization of apical
MyoII propagation wave (Fig. 1B) [27].

Importantly, this model differs from the mesoderm by the fact that MyoII activation and cell invagination is initiated in a specific region and propagate directionally. On the contrary, apical constriction starts stochastically in a salt and pepper pattern in the predetermined domain of the mesoderm, defined by the expression of Snail and Twist, then extends to the whole mesoderm. Another difference is the implication of directional tissue flow due to tissue curvature and the local resistance that contribute to the polarized wave of MyoII accumulation during endoderm invagination, while no such mechanisms have been observed during mesoderm invagination.

It would be interesting in the next future to consider the potential impact of these apical forces on the nucleus in these two model systems and decipher how nuclei respond to apical mechanics. Indeed, so far, only nuclear movement has been considered in the mesoderm. In this model, it was shown that apical contractility and apical surface reduction creates a cytoplasmic flow that relocate the nuclei basally [28,78]. Since the nucleus is a mechanosensitive organelle, it is tempting to speculate that morphogenetic forces could strongly impact nuclear mechanics.

## 2.2. Force transmission in 3D

Another example of force propagation comes from the study of apoptosis dependent folding processes. This includes leg disc distal folding in *Drosophila* and neural tube dorsal folding in chicken. In the leg disc, cell death by apoptosis occurs in a ring-like domain prefiguring the future fold. These dying cells, around 20 % of the future fold domain, contribute to the folding process through the generation of an apico-basal force generated through the formation of a linear structure of acto-myosin spreading from the apical adhesion belt to the basal nucleus. This force is transmitted to the neighboring cells through the transient deformation of the apical surface of the epithelium and result in an accumulation of apical myosin in the closest neighbors [64]. This transmission is revealed by the diminution of apical myosin in the fold domain when apoptosis is impaired. In addition, ectopic induction of cell death is sufficient to induce transient apical deformation and the formation of supracellular apical cable of myosin in the neighboring cells, a redistribution that is absent when apoptotic cells are unable to generate forces [64]. This apoptotic morphogenetic force is conserved during neural tube closure in chicken. Here again, apoptotic cells generate an apico-basal force that deforms the apical surface of their closest neighbors, a deformation that becomes less and less important with time. This suggests that tension build up in the neuroepithelium through the progressive stabilization of the deformation in a rachet-like folding process [79]. The molecular mechanism underlying this transmission remains unknown. However, the persistence of strong adhesion between the dying cell and its neighbors suggests that mechanical feedback (transmission of forces to the neighbors) is mediated by the mechanosensitivity of these junctions (Fig. 1C).

This propagation of forces is further amplified by a channeling pro-
cess driven by Arp2/3 and the planar polarization of the tissue, ensuring
fold robustness in the *Drosophila* leg [58]. Interestingly, the neuro-
epithelium is also strongly polarized [68] suggesting that force trans-
mission could be biased in this tissue too. This hypothesis would be

interesting to test in the future, with the development of new techniques
enabling the non-invasive measurement of forces during morphogenesis
such as micrometric force sensors [54] or force inference in 3D [37].

Thus, apoptosis dependent folding relies on sporadic apoptotic cells
in a restricted domain of the tissue that pull on their neighbors, leading
to a global increase of apical myosin in the future fold domain. This
process is reminiscent of what was observed in the mesoderm, with a
subset of cells initiating the folding process by generating a mechanical
signal (either planar constriction in the mesoderm or orthogonal
contraction in apoptotic cells). This creates a pulling force on the sur-
rounding cells that respond by apical myosin II accumulation and
folding (compare Fig. 1A and C).

These studies highlight that forces are generated and transmitted not only within the plane of the epithelial sheet, but also in three dimensions. This has been nicely illustrated by a recent work dissecting the propagation of MyoII waves in individual cells using lattice light sheet microscopy and showing that contraction could originate from anywhere in the cell and propagate in any direction [89]. Another example of force propagation along the lateral membrane of epithelial cells came from a study of cephalic furrow formation. In this model, it was shown that mechanical forces can help ensuring robustness to a very stereotyped morphogenetic process through the coordination of lateral contractility of a row of cells. Indeed, cephalic furrow depends on the overlapping expression of the two transcription factors Buttonhead and Even-skipped, which is forming a wavy line of cells. This noisy genetic code is corrected thanks to the mechanical coupling of cells along the furrow, through planar polarized MyoII ribbons forming along their lateral membrane thus ensuring the formation of a straight invagination [23]. This work nicely illustrates how mechanics can ensure the invariance of a morphological trait during development (Fig. 1D).

If forces can propagate from cell to cell, they can also have cell autonomous impact. The apoptotic forces described above have been shown to rely on the anchoring of an actomyosin linear structure across the apico-basal axis of the cell, spreading from the apical adhesion belt to the nucleus. Importantly, this tight connection leads to nuclear fragmentation upon actomyosin contraction [3,65,79]. This example illustrates quite well that intracellular forces can impact the nucleus, and in this case, contribute to its destruction. In non-apoptotic cells, it is now well established that forces also impact the nucleus, although in a less dramatic way. Indeed, the nucleus is the largest organelle and has been proposed to act as a sensor of constraint during migration [53].

In the following part of the review, we discuss recent literature regarding mechanical impact of forces on the nucleus. We first explored what is known about the characterization of nuclear physical properties, then about the nuclear mechanical response, from protection mechanisms, to adaptive responses and potential damage.

## 3. Force propagation across cell: mechanical impact on the nuclear envelope

### 3.1. Nuclear physical properties

The nucleus behaves like a viscoelastic material, exhibiting both solid-like and liquid-like properties [35,36]. Its elastic nature, resembling that of a solid, enables it to regain its original shape after deformation by a force. In contrast, its viscous, liquid-like component resists returning to its initial shape, allowing for more permanent deformation. The balance between these two behaviors is set by the type (rate and amplitude) of the force applied and by the different components of the nucleus including the nuclear envelope and the nuclear content. We will focus here on the nuclear envelope and the associated macromolecular networks.

#### 3.1.1. Lamins as a major nuclear shield

The nuclear envelope plays a protective role in safeguarding the
nuclear content, a function largely attributed to the nuclear lamina, a
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Balance of forces at the nuclear envelope: from nucleus homeostasis to force unbalance. A. Nuclear dynamics depends on the balance between internal and external forces and the mechanical properties of the nucleus and cytoplasm. At equilibrium, forces are balances between internal pressure, nuclear envelope resistance due to membrane and nuclear lamina properties and chromatin state. B. External forces can disturb this balance leading to nucleus inward deformation. In contrast, when the internal pressure changes due to chromatin decondensation, the nucleus blebs. C. In both cases, if the curvature of the nuclear envelope becomes too pronounced, lamin B can no longer anchor to the envelope, weakening its resistance and potentially leading to nuclear rupture. D. In extreme cases, following caspase activation, lamins are weakened and cytoplasmic forces pull on the nucleus, while chromatin condenses in response to caspase stimuli. This imbalance culminates in nuclear fragmentation.</figcaption></figure>

dense fibrillar network primarily composed of type V intermediate filaments known as lamins. These proteins are evolutionarily conserved [69] and are categorized into two major types: lamin A/C and lamin B [47]. Lamin B is expressed ubiquitously and essential for development, with its absence resulting in embryonic lethality in mice [11,90]. In contrast, lamin A/C is not present during early development but gradually accumulates in mechanically stressed tissues, as shown in mouse tissue extract ranging from brain to bone [87].

Each lamin type has distinct functional roles. Lamin A/C contributes significantly to the elastic properties of the nucleus, restricting its deformability, as demonstrated in micropipette aspiration experiments [15]. Accordingly, lamin A/C is closely associated with nuclear stiffness. In *ex vivo* cultured embryonic chicken heart tissue, lamin A/C helps the nucleus resist to high mechanical forces [13]. Its concentration scales with substrate or tissue stiffness both *in vitro* [9] and *in vivo* [87], thereby offering mechanical protection in load-bearing tissues. Conversely, on soft substrates, Lamin A is phosphorylated and subsequently disassembled, indicating a dynamic adaptation to mechanical cues [86]. While the ratio of lamin A/C to lamin B was initially proposed to determine nuclear envelope stiffness [86], a more recent study found that depleting lamin B can actually increase nuclear stiffness in cell types with low levels of lamin C [84]. Consistently, Lamin B plays a role in nuclear stiffness during early development in *Drosophila* embryos particularly where lamin A/C levels are low [30]. Collectively, these findings highlight the nuclear lamina as a crucial structural component that shields the nucleus content from mechanical stress.

### 3.1.2. *Tight connection between lamina and chromatin*

While the nuclear lamina is a major determinant of the nucleus's elastic properties, recent micromanipulation studies of isolated nuclei have shown both lamina and chromatin contribute the viscoelastic properties of the nucleus [84]. Both are tightly interconnected and lamins play crucial role in chromatin organization and dynamics [7,8]. Indeed, studies in *Drosophila* and mammals have demonstrated that depletion of lamin A/C or lamin B alters nuclear organization, impacting in particular the compaction of topologically associated domains which govern the spatial organization of the chromatin [88,94]. Chromatin is organized into two compartments: a gene-dense compartment, rich in euchromatin and transcriptionally active, generally found in the central region of the nucleus, and a gene-poor compartment, rich in heterochromatin and transcriptionally repressed, typically located at the nuclear periphery. At the nuclear periphery, the chromatin interacts with the lamina. This tethering to the nuclear periphery impacts nuclear stiffness, forming a buffer that attenuate the impact on the more central region of the nucleus, as observed in yeast [81] and human cell lines [67]. Interestingly, both short-term and long-term adaptive responses to cyclic stretch have been reported, underscoring the importance of temporal dynamics in this mechanical response [67]. In addition, the state of chromatin condensation contributes to nuclear physical properties. It was shown that chromatin stiffening via the DNA intercalator propidium iodide modifies the mechanical response of the nucleus making it 4 folds less deformable. Similarly, alteration of chromatin condensation state by alterations of histone modifications modulates the nuclear mechanical response to stretch. Thus, chromatin decompaction
decreases nuclear stiffness, while chromatin compaction increases it [84]. Overall, the chromatin thus contributes to its own protection by providing mechanical support to the nucleus [83].

The physical properties of lamins and chromatin also depend on the magnitude of the applied force. Interestingly, chromatin governs the response to small deformations, while the nuclear lamina provides a response to larger deformations [84]. Complementary experiments have shown that chromatin also behaves as a viscoelastic material, with its properties varying depending on the extent of deformation. Experiments using magnetic beads of different sizes have shown that at the nanometer scale, chromatin exhibits fluid-like behavior [44] whereas at the micrometer scale, it demonstrates solid-like properties [16].

## 3.2. Force unbalanced at the nuclear envelope

### 3.2.1. Nuclear deformation

Given the mechanical properties of the nucleus described above, its response to cellular forces depends on the balance of forces at the level of the nuclear envelope, as schematized in Fig. 2A [41,59]. The resulting impact on the nucleus can have wide-ranging effects, influencing key nuclear characteristics such as positioning, shape, and volume [6,48]. It can also affect nuclear activity, including transcriptional state and internal nuclear organization, which has been thoroughly examined in previous reviews [20,36].

Here, we focus on the balance of forces acting on the nuclear envelope. When a balance is maintained between internal pressure, membrane tension, lamina stiffness and the chromatin condensation state, the nuclear envelope has a smooth and regular shape (Fig. 2A). However, when this balance is disrupted, this results in nuclear envelope invaginations or bleb formation, as illustrated in Fig. 2B-C [38,73]. This unbalance can lead to a redistribution or remodeling of lamins, which accumulates around small deformations (Fig. 2B). However, when membrane curvature becomes excessive, lamin B is destabilized and loses its structural role [71], which prevents it from conforming to highly curved regions and could lead to nuclear envelope rupture (Fig. 2C).

Similarly, Lamin A often accumulates at the site of deformation where curvature is not too strong [38,82]. This local enrichment of lamin A suggests a localized stiffening of the nuclear envelope, potentially serving to resist rupture [33]. This localized response is consistent with what has been observed at a larger scale in cardiac cells, where lamin A levels increase in response to mechanical stress, helping to protect the nucleus from rupture and DNA damage [13].

### 3.2.2. Nuclear rupture

Seminal works on nuclear rupture come from the observation that spontaneous ruptures occur in cells migrating *in vitro* in a constraint microenvironment [17,75]. It is quite surprising to observe migrating cells go spontaneously through narrow opening, putting at risk nuclear and genome integrity. Indeed, when rupture occurs, the cytoplasm and nucleoplasm come into contact, which can lead to DNA damage. Although nuclear ruptures are rare events *in vivo*, certain conditions increase their occurrence, in particular in tissues subjected to significant mechanical stress, as shown for example during immune cell migration in narrow spaces in *Drosophila* [43] or in migrating neurons where lamin B has a protective role preventing nuclear rupture [11]. Interestingly, in embryonic cardiomyocytes in mice [80], it has been suggested that ruptures may serve as a selective mechanism, favoring cells with strong repair machinery, thereby preparing the tissue for its functional needs in adulthood. Rupture frequency also coincides inversely with lamin A/C levels as shown in muscle cells and supported by *in silico* data [21,77], but can also be favored by Lamin B depletion as shown *in vivo* in *Drosophila* border cells [70]. Interestingly, after rupture, the nuclear envelope can be repaired through the recruitment of the ESCRT III complex [17,75]. The whole process of nuclear rupture and repair have been observed in human tumors, suggesting that this process occurs *in vivo* when cells have to migrate in narrow spaces and could drive invasiveness [17,66].

Overall, nuclear envelope ruptures are the consequence of excessive perturbations of force balance at the nuclear envelope [2]. This could be due to different factors creating inward or outward forces, including forces applied by the cytoskeleton through the LINC complex, chromatin state, nuclear envelope curvature, nuclear internal pressure (see below).

Chromatin organization has been proposed to play a key role in maintaining nuclear envelope integrity. In response to mechanical stretch, the nuclear content undergoes significant remodeling, including a reduction in peripheral heterochromatin marks. This reorganization helps protect genome integrity by insulating active chromatin within the central region of the nucleus [67]. Moreover, depending on its condensation state, chromatin can exert inward or outward forces on the nuclear envelope [84,85], contributing to the overall force balance. These forces were proposed to either stabilize the nucleus and prevent rupture or, conversely, promote rupture. (Fig. 2C).

Nuclear envelope rupture is also influenced by the curvature of the nuclear membrane. Early evidences show that nuclear indentation frequently leads to rupture, suggesting that high curvature may promote membrane failure [13,92]. This was further confirmed by the analysis of curvature impact on nuclear rupture when cells are submitted to different types of challenges. This includes iPS-derived progeria patients cells in which lamin is reduced, or conditions where cells were challenged mechanically such as beating chick embryo heart cells or cancer cells with multi-site rupture after migration through small pores [71, 72]. Additional support comes from observations of nuclear indentations, lamina dilution, and subsequent rupture upon nuclear contact with lipid droplets [38].

Nuclear envelope rupture is also influenced by the internal pressure of the nucleus, which is governed by nuclear volume and content. This internal pressure must be well balanced by nuclear envelope resistance, governed by membrane tension and lamina stiffness [41,62]. Additionally, external forces, such as those generated by the actomyosin network, microtubules, or the surrounding microenvironment, can further impact this balance and contribute to rupture [32,33,40]. Indeed, these ruptures have been shown to depend on functional contractile actin network anchored to the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, underlying the importance of cytoskeleton forces in the rupture process [34].

Finally, another element to take into consideration to understand the origin of nuclear envelope rupture is the turn-over and dynamics distribution of the different components of the nuclear envelope and associated proteins. The nuclear envelope is a dynamic structure. Composition of the lamina is permanently changing as shown by the accumulation of lamin in response to local deformation [38,82], but also by changes in lamin conformation in response to shear stress or by the regulation of lamin stability by phosphorylation [86]. The nuclear pore complex (NPC) localization can also vary in response to lamin concentration as shown recently in *Drosophila* tissue by the clustering of NPC in lamin depleted cells [12]. Finally, the LINC complex assembly and disassembly is regulated at multiple levels. This includes calcium dependent trimerization of SUN proteins and the interaction between SUN and KASH proteins, which regulates the stability of the LINC complex. These regulatory mechanisms make the connection between cytoskeleton and nucleoskeleton highly dynamic [60].

## 3.3. Orchestration of nuclear destruction: Nuclear collapse in apoptotic cells

As mentioned above, the nuclear envelope has a protective function and is usually repair following local ruptures. Alterations in nuclear homeostasis are associated with cell invasiveness and cancer, but also with a wide range of pathologies and with aging [76], highlighting the importance of maintaining nuclear envelope integrity. For example, reduced lamin B expression is associated with Alzheimer's disease. In
Box 1

**Solid:** a solid material has a fixed shape and volume. Its constituents are closely packed and resist deformation.

**Elasticity:** Some solids are elastic, meaning that they can deform under stress and return to their original shape when the stress is removed. Elasticity does not depend on the rate of the applied stress or strain.

**Stiffness:** measure of the resistance to deformation: k = Force/Deformation. A stiffer material deforms less when subjected to the same stress.

**Liquid:** a liquid material has a fixed volume but no fixed shape, adapting to the shape of its container. Particles are loosely connected, allowing flow under stress.

**Viscosity:** describes a fluid's resistance to flow. Higher viscosity means slower flow because of greater internal friction of the fluid's particles.

**Viscoelastic material:** substance exhibiting both elastic and viscous behavior. Viscoelastic materials store and dissipate energy depending on the timescale of the applied stress.

**Pressure:** The force exerted per unit area on a surface.

addition, mutations in lamin A leads to a group of disorders known as laminopathies, including Hutchinson-Gilford progeria syndrome. However, nuclear envelope may have to collapse in some specific contexts such as apoptosis (Fig. 2D).

Apoptotic cells exhibit nuclear envelope rupture and DNA leakage, both of which are strongly suppressed by the inhibition of pan-caspase [46]. Structural proteins of the nuclear envelope are targeted by the caspase, including lamins A/C and B1, some nucleoporins and LAP2-α and LAP2-β [51]. However, the cleavage of these proteins may not be sufficient to induce the disintegration of the nuclear envelope. Indeed, the expression of non-cleavable forms of lamins A or B delays apoptosis but does not block nuclear collapse. Actomyosin contractility appears to be necessary on top of lamin cleavage to trigger nuclear fragmentation (reviewed in [65]). Thus, the fragilization of lamins has to cooperate with the generation of actomyosin dependent forces to lead to nucleus collapse. This is further supported by recent finding showing that Lamin A degradation is reduced in cells treated by the ROCK inhibitor Y-27632, indicating that forces contribute to the fragilization of nuclear lamina [4]. Nuclear permeability is also altered through the cleavage of NPC components [24,51]. Since nuclear pore permeability can also be altered mechanically in living cells [22], it is tempting to speculate that forces could also contribute to nuclear pore leakage during apoptosis. Finally, nucleus permeabilization leads to chromatin condensation, which further favors nuclear collapse by the generation of inward forces [31]. Taken together, these in vitro studies strongly suggest that mechanical forces play a role on nuclear envelope dismantlement and the orchestration of nuclear collapse.

Recent data further suggest that apoptotic nuclear dismantling occurs through an imbalance of forces in vivo during morphogenesis. Indeed, as mentioned above, in both *Drosophila* leg and chicken nervous system, at the onset of apoptosis, a linear structure of acto-myosin is formed in columnar epithelial apoptotic cell. This structure, connecting the apical surface of the dying cell to the nucleus, eventually contracts leading to the movement of the nucleus from basal to apical [3,79]. Interestingly, deformations have been observed at the level of the nuclear envelope during the generation of this apoptotic force, suggesting that force imbalance could be at the origin of the subsequent nuclear collapse. Consistently, the expression of a DN form of Rho is sufficient to significantly reduce nuclear fragmentation [79].

Interestingly, a recent work analyzes the consequences of forces imbalance on nuclear collapse in *c. elegans*, in physiological contexts. *c. elegans* has the advantage of having a single gene coding for lamin LMN-1. They generate a degron-tagged *lmn-1* allele, viable and fertile in the absence of auxin. In the presence of Auxin, LMN-1 is reduced, the nuclear envelope stiffness decreases (as shown by measurement on isolated nuclei from dissected gonads) and the oocytes display nuclear collapse. Interestingly, the depletion of lamin induced an asymmetric localization

of the LINC complex during meiosis and obvious deformation of the nuclear envelope, shortly preceding nuclear collapse. In addition, they show that this nuclear collapse can be rescued either by mutations in the dynein complex (dynein light chain DLC-1 or the dynein activators DNC-1 and LIS-1) or in the LINC complex components (SUN-1 or ZYG-12), indicating that the collapse is driven by asymmetric forces acting on nuclei through the LINC complex [52]. Although this process appears to be independent of apoptosis, these findings underscore the critical role of force balance in maintaining nuclear integrity. They further suggest that during apoptosis, a disruption of this balance (potentially due to lamin depletion) may lead to uneven force distribution on the nuclear envelope, resulting in mechanical imbalance, envelope fragilization, and eventual collapse (Fig. 2D).

Nuclear envelope is also largely remodeled during mitosis. Different types of nuclear envelope rearrangements occur from local remodeling to allow nuclear envelope expansion (close mitosis) to nuclear envelope breakdown (open mitosis) [91]. Interestingly, local and global nuclear envelope breakdowns occur in a similar way, with a key role of Les1 as insulator, ensuring the separation of nucleoplasm and cytoplasm [18]. Here again, the balance of forces seems to play an important role in nuclear envelope rupture with a close association of chromatin with the LINC complex [26] and the ESCRT machinery that ensure that nuclear envelope rupture remains local around the spindle pole body [1].

Altogether, these data suggest that nuclear envelope rupture is driven by similar mechanisms in the different contexts mentioned above, with a key role of the balance of forces applied on the nuclear envelope.

4. Discussion/perspectives

In this review, we summarize recent findings on force propagation, with a focus on how mechanical forces are transmitted across epithelial tissues. One mode involves planar force propagation through an integrated network of actomyosin and cell-cell adhesion sites, a process that is notably influenced by tissue curvature. Forces can also propagate in three dimensions—for example, through apico-basal transmission driven by forces generated in dying cells, or via myosin II waves traveling along the epithelial cortex in 3D. In addition to these tissue-scale mechanisms, we also highlight how mechanical forces affect the cell interior, particularly the nuclear envelope. These effects range from changes in envelope stiffness to compromised integrity and, ultimately, nuclear collapse.

An important open question is about the impact of forces at the nuclear envelope and the consequence in term of transcriptional dynamics in physiological contexts. While it is now established that nuclei can respond to mechanical forces, how this influences overall cellular behavior within a living organism remains poorly understood. Since
<figure><img src="image_7.png" /><figcaption>**Fig. 3.** Interplay Between Mechanical Forces and Transcriptional Regulation Across Tissues. Hypothetic scheme summarizing how forces generated and propagated during morphogenetic processes could affect nuclear dynamics and transcriptional activity across tissue. While it is well established that physical forces affect the nucleus, how this response shapes cell fate at a tissue scale is unclear. Force propagation to neighboring cells could non-autonomously affect their nuclei and transcriptional dynamics, potentially homogenizing tissue responses, reducing developmental noise, and increasing the robustness of morphogenetic processes. Nuclear changes could further create feedback loops that amplify mechanical signals or directly influence the fate and behavior of neighboring cells, adding another layer of coordination across tissues.</figcaption></figure>

force propagate across tissues, how far can cells be influence tran-
scriptionally? Could force propagation contribute to the homogeniza-
tion of cell response and the reduction of developmental noise? A recent
work suggests interestingly that transcription can be influenced non-
autonomously by neighboring tissue movements. Indeed, Notch
responsive enhancers activity is delayed in the neurectoderm if meso-
derm invagination is impaired in *Drosophila* embryos [25]. If there is no
direct proof that the impact is non-autonomous and strictly dependent of
physical forces exerted in the neighboring tissue, this work interestingly
suggests that forces can have a broader influence than previously
anticipated. It is tempting to speculate that this type of non-autonomous
transcriptional impact could be a way to ensure the coordination of cell
behavior within a particular domain or between two adjacent and
interconnected tissues (Fig. 3 recapitulate these hypothesis).

Another interesting open question remains regarding the physio-
logical impact of the nuclear envelope ruptures described above and
observed when cells are challenged by their environment. Since these
ruptures occur *in vivo* and since they can be repaired, this could greatly
influence the cellular outcome. Could these ruptures influence cell fate
or the migratory behavior of the cells? Finally, since forces can also lead
to severe damages, one can postulate that this could drive apoptosis and
potentially influence the pattern of apoptosis in a tissue particularly
challenged mechanically. Since apoptosis can be induced by over-
crowding or compressive stress [10,49,61], one can ask whether this
induction could involve a nuclear sensing of compressive stress. Alto-
gether, the data summarized here suggest that we still have a lot to learn
on the integration of forces in living systems. Better understanding how
nuclear mechanics impact morphogenesis plasticity and robustness will
constitute the challenge of the coming years in the field.

Declaration of Competing Interest

The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.

Acknowledgements

MS's research is supported by the Center National de la Recherche
Scientifique (CNRS), the University of Toulouse and funded by grants
from the National Agency of Research (ANR, PRC AAPG2021, CellPhy),
the Research Association against Cancer (ARC, Programme Labélisé
AAP2020, ARCPGA12020010001154_1591) and the Medical Research
Fundation (FRM, Equipes FRM, EQU202403018134). We thank Tatiana
Merle for constructive comments on the manuscript.

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