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Home , Cell nucleus, Nuclear envelope, Nuclear lamina

o wf n ensE Discher* E. Dennis and Swift Joe in elasticity ECM to mechano-responsive mature is lamina nuclear The COMMENTARY ß Ato o orsodne([email protected]) correspondence for *Author Philadelphia, Pennsylvania, in of USA. University heads 19104, Lab, PA Biophysics of collision and Molecular a during as such tissues soft impact, when to from Nonetheless, protected subjected . are our are marrow, by their and stresses brain and because of as shocks some robustness such Furthermore, tissues, load. for softest bear to need our them 2013). require less al., not have does et function be (Henderson tissues even nuclei softer of their might Our and strains deformations cells local Tissue-level within and 1995). amplified 1999), al., et al., (Guilak et (Aletras strain , radial experiences wall and during 20% ventricular stresses left running, a the shocks, heartbeat, or to high-frequency every to With resistant walking strains. subjected and mechanical as are robust they such the them which muscle exertion, making to skeletal physical stiff, cartilage, are resistant routine bones, tissues Our particularly . Mature and active be viability. an course, of to of demands their and, need fulfill to efficiency tissues organs optimal and tissues with our roles driven likely has Introduction Proteostasis Nucleoskeleton, Nucleus, , Extra-cellular Mechanotransduction, mechanics, Cell WORDS: KEY stress-induced from protecting niche damage. in hematopoietic role a mechanics in emphasizing development, nuclear as mechanics for well during as metastasis, nuclear motility cancer and ECM of differentiation cell of work importance and recent combination discuss the anchorage a also highlights will to We that cues. response levels molecular in upon and mechanics mechanisms. regulate decisions impact that epigenetic cell-fate also pathways that and broader signaling the and and as summarize envelope line entry We nuclei nuclear that factor the of lamin of filament properties inside intermediate the mechano-responsive the Commentary, by the this matrix determined In extracellular tissue. review the developing and of we mature elasticity both studies the in recent to (ECM) most actively response are our itself in nucleus and the controlled of emerging, properties expression. mechanical are the that factors nucleus show transcription cell into of the entry signals into the mechano-regulate transduce that focused that Pathways efforts research mechanisms current with of on years, been many has withstand for surroundings and interest immediate meet great their to of order demands in physical cues the physical to respond cells How ABSTRACT 0 loocri h atlg fke onswt vr step every with joints knee of cartilage the in occur also 20% 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,30–05doi:10.1242/jcs.149203 3005–3015 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. ehnclpoete soitdwt hstnn flamina of the tuning in this with nuclear to associated changes of properties cell Corresponding 2013b). cultured mechanical concentration al., in et re-capitulated (Swift the partially systems between More was scaling and 2013b). that systematic nucleoskeleton al., elasticity a et discovered (Swift tissue also tissues we elasticity mouse tissue surprisingly, for bulk between and discovered correlation components the close was ECM to A of subjected 2013b). increasing concentration al., are the of et that (Swift tissues tissues stress in in greatest implication, (ECM) by and matrix stiffness, extra-cellular and cells can 2005). straining al., rapid et (Viano of damage occurrences lasting rugby, cause or football American tutrsta ufl motn tutrlrls(erane al., et (Herrmann roles filamentous structural coiled- 2009). higher-order important form into fulfill lamins assemble that the structures that filament , dimers intermediate and parallel other keratin coil 2010; Like as al., lamins such 2012). et proteins, from Lammerding, Dechat cleaved by B-type and is example, Ho that for group with (reviewed, lamin-A farnesyl in mature a differ modification, by they appended but indeed, permanently sequence, post-translational and, acid features amino their in structural similarity share some lamins have The lamins. the spliced by type’ encoded are alternatively lamin-B2 most and LMNB1 lamin-B1 are and lamins; ‘A-type’ lamin-C as mice to the and from humans, expressed of lamin-A are of nuclear products : cells the lamin of three somatic inside forms main the just the , the In lies and chromatin 1A). it both (Fig. with and interacts and proteins, envelope to lamin continue filament pathways regulatory recent field. and or the great challenge 2006) despite into transcriptional transduced al., are However, signals specific et mechanical 2000). 2000), how proliferation al., of Engler al., questions 2012), et progress, 2004; et Lo al., (Wang al., 2009; et al., et et Raab (Engler Klein 2009; 2009a; differentiation al., al., al., et et et (Hadjipanayi (Hadjipanayi migration Winer a 2005), 2009b; al., as et (Discher including a described phenomena, contraction uncovered cellular sensitive has mechanically other been studies of mechanobiological but host 1987), in classically (Frost, explosion regulation recent has a of context new the demands of in ‘mechanostat’ rate physical the of properties to mechanical in control of of matching or pathways composition Responsive production. into remodeling, protein ECM feedback and or implies turnover cell the environment protein the into of to and regulation response cytoskeleton active transmitted the An are the across that nucleus. protect surroundings, shocks to from the nucleus act through the might of response cargo this chromatin that suggest composition ehv eetysuh ocaatrz h opsto of composition the characterize to sought recently have We h aiai ewr tutr omdfo intermediate from formed structure network a is lamina The and LMNB2 LMNA ee,rsetvl,adaekona ‘B- as known are and respectively, genes, ee n hyaecletvl referred collectively are they and gene, 3005

Journal of Cell Science el ntal xrs elgbeqatte fAtp ai rtis u hs eesices stencessifn uiglnaecommitmen lineage during stiffens nucleus the as emb increase Right: levels 2013). al., these ti bl micro-elasticity et but adult brain, Majkut determine proteins, in 1987; (e.g. to al., lamin made soft aspiration et A-type observations remained 2007). (Lehner micropipette of lamins Left: either al., by A-type quantities (C) tissues et and probed negligible 2013b). collagen divergent were of express al., but A levels initially et predominantly soft, increased chick cells (Swift by contains initially developing accompanied tissue lamina was Inset: is The soft disc proportion development red). mechani microelasticity. in during embryonic is defines heart, tissue stiffening lamina the it tissues (e.g. to nuclear that chick; in stiff proportional expected the developing present increasingly is perhaps, in the collagen lamina became is, prevalent from I nuclear it are body, results type the the lamins with of in in B-type lamin quantity consistent proteins whereas B-type the prevalent tissue, to Left: most stiff lamin the (B) of A-type in Science). one of Cell is ratio of collagen the Journal As Right: 2013b). The al., in et published (Swift originally micro-elasticity 2010a, al., et Buxboim COMMENTARY 3006 alternative are lamin-C, and l lamin-A the lamins, cytoskeleton, A-type the The and view). chromatin magnified between the interface in an (shown at complex located LINC effectively the the are through of they lamina products envelope; the spliceoform development. nuclear to during the attached and of is tissue inside mature which in the lamin on and networks ECM the juxtaposed between Relationship 1. Fig. A C B A- andB-typelaminsassemblebetweenthenuclearenvelopechromatin Log (micro-stiffness) Tissue stiffens indevelopmentandsodoesthenucleus Lamin-A scaleswiththecollagen-dependentstiffness ofmaturetissues Embryonic disc Embryonic Heart Brain heart Embryo age(days) aspiration Micropipette

LMNA Log (type I collagen) stifftissue High collagen Brain ee h -yelmn,lmnB n ai-2 r rti rdcsof products protein are lamin-B2, and lamin-B1 lamins, B-type the gene; Liver F- Log (micro-stiffness) Intermediate filaments Adult range Adult range Adult Kidney Nucleus Fat Nuclear pores Cartilage Muscle Bone Log (type I collagen) Heart A-type lamin Very low Chromatin Chromatin Embryo age(days) Heart Brain LMNA LMNB2 LMNB1 Lamin proteins Coiled-coil domains ora fCl cec 21)17 0531 doi:10.1242/jcs.149203 3005–3015 127, (2014) Science Cell of Journal

Log (A-type:B-type lamin) Chromatin envelope Nuclear lamin A-type High lamin A-type Low Marrow A-type lamindominant A -yeadBtp ais(e n le epciey form respectively) blue, and (red lamins B-type and A-type (A) Brain Log (micro-stiffness) Liver SUN proteins A-type lamin B-type lamin Nesprins Ig- Common region proteins Cytoskeletal B-type lamindominant Fat Kidney LMNB1 Lamin-C Lung Pluripotent

Relative nuclear stiffness Lamin-B2 Lamin-B1 complex LINC Lamin-A lamina Nuclear and Cartilage Muscle A-type lamin Very low Time inculture(days) LMNB2 Heart Bone epciey(dpe from (adapted respectively , differentiation Stem cell ide tissue Middle: . Fibroblas e or ue) (Pajerowski t a properties. cal tp lamins -type seare ssue yncstem ryonic lt tissue to al te of atter t

Journal of Cell Science nrae n h ulu eoe orsodnl stiffer correspondingly becomes lamin-C nucleus and panel). lamins right the these lamin-A 1C, of (Fig. levels of and the fate, these levels lineage-specific As increase, a 2007). low to al., et commit 1987). have be Pajerowski cells to 2013; al., to shown al., et et been and (Eckersley-Maslin indeed, (Lehner have, soft lamin-C cells very stem and embryonic correspondingly lamin-A have in ECM stiffening to Nuclei of likely in as also levels Cells are stiffens 2013). heart, the higher heart the al., as et However, the such (Majkut tissues, whereas deposited panels). soft, are with with proteins middle development, remaining during of brain and diverge soft, the tissues levels different left very low of properties 1C, initially correspondingly (Fig. indicating is collagen profiles 2013); disk al., proteomic the embryonic et that showed (Majkut tissue homogeneous chick determined embryonic of been aspiration micropipette also has development across variations systematic on perspective tissues. Ro new many 1981; a al., al., et provide Krohne et they 1992; Broers al., (e.g. et with quantification Cance agreement lamin 1997; 30-fold on in literature broadly bone. a extensive are to an brain observations by from recent of lamin dominated our A-type families Although of is concentration main the scaling two in increase compositional these between A- the of ratio primarily lamins, content Although the the panel). its by right with of 1B, characterized terms correlated (Fig. lamins in strongly B-type lamina and is type nuclear tissue the bulk found of we of composition and elasticity nucleus, the and cytoskeleton that the in proteins abundant COMMENTARY cl ihtsu lsiiy(wf ta. 03) Mass 2013b). al., et quantify to (Swift used elasticity also proteins was tissue ECM-associated mass we other spectrometry 2013a), label-free with and al., collagens quantitative et scale that (Swift using shown profiling By have proteomic al., panel). for et spectrometry left elasticity (Gardel tissue of polymers’ 1B, basis the (Fig. ‘biological the is concentration as increased their behave determining higher 2004), expectation to at an largely with proteins found consistent where, for are tissues bodies, mature Collagens stiff in tissue. our levels of properties in most the mechanical are proteins ECM the of prevalent constituents protein other and and Collagens mature in components tissue lamina developing and ECM of Scaling aiaadhnepooe htlmnat sbt h guardian the to both the as chromatin. seeks acts of of gatekeeper lamin role Commentary the that mechanical and proposes This the hence al., of and 2013). et influence lamina be al., pervasive Kim to the it (e.g. et highlight led regulation the Meuleman has epigenetic of 2011; nucleus proximity with the The associated the within tissue. widely limit through properties move to such to lamina cells that we of evidence and freedom nucleus, recent the as summarize bulky of will and consequences stiff regulatory a function additional such protective are possessing there primarily into lamin, a the nuclear on cell mechanotransduction of of focus linking regulation the in we active role Although of broader the pathways. its surroundings of and terms the itself in lamina and mechanical both transducing ECM responses, will in cellular the we lamina and from the detail, of signals in functions tissue nuclear elaborated the on be consider with lamina the will systematically of properties composition mechanical the vary of effects that The stiffness. proteins the characterize h eainhpbtentsu tfns n C during ECM and stiffness tissue between relationship The hsCmetr ist umrz eetefrsto efforts recent summarize to aims Commentary This , 0 ftemost the of 100 bre l,1990), al., et ¨ber h adcl al fteeognsslkl rtc the protect with likely cells for possible these not . is of cell that soft manner walls a . in cell of chromatin those than possessing hard complex latter more The the and larger and despite are 2011), that in Misteli, expressed that not and consistent are fact (Dittmer is lamins viability that the cell notion current for the Nonetheless, essential differentiation with absolutely lifespan. and not are trafficking the lamins of throughout during cell nuclear processes during maintain continue the as for and such and regulate development, compensated to of migration, need stages might some a be here during still distinction structure is perhaps the there that blurred; and can note be we cultured absence However, development. 2013). organisms, be its higher the al., in fine-tune tissues to and can maturing et be of therefore regulation (Kim might and lamin cells properties of lamins al., role crucial any stem et most The having Likewise, (Kim embryonic without 1999). embryogenesis al., differentiated and survive et ECM (Sullivan mice 2011), with not tissues knockout are all conjunction lamin-B lamin-C form A-type and lack (in still that lamin-A mice lamins knockout fate 2013b), because development, al., to cell essential et (Swift animal elasticity) of decisions reta aioahe as eet ntsusweeA-type where tissues in defects broadly cause is it question, this that resolve to true needed Although widely is symptoms. a work tissue-specific further such much cause which can by of protein aspects mechanism confounding expressed the the is 2000; of disease one al., ‘’; Indeed, lamin-related (termed 1999), 2008). et al., al., premature et Shackleton and Merideth et 2000; 2000) al., (Fatkin al., et Speckman et cardiomyopathies 2013; (Hegele 1999), dystrophies Lammerding, lipodystrophies muscular al., include and et disorders (Bonne Isermann These Davidson 2012; 2012). 2014; al., Worman, lamins et Lammerding, A-type Butin-Israeli in by and substitutions example, acid for amino (reviewed, single 2014). al., or al., et truncations et Harada (Rowat later; (discussed circuits pores transwell microfluidic or 2013) through deformed are been migration nuclei has where 2006), viscosity during studies al., nuclear nuclear in on et demonstrated for lamins recently Lammerding maintaining A-type more appreciated 2004; of al., been influence in et the has and Broers lamins viability (e.g. years cell water. A-type to many with and akin filled integrity of one be structural to stoichiometrically importance might honey is with lamins The filled lamina B-type balloon the versus a comparing which A-type difference the in by Thus, al., 2013b). dominated et nucleus al., (Harada et a Swift viscosity 2013; between the al., et nuclear to Shin response contributing 2014; The elastic lamins the 2013b). A-type to primarily and al., contributing properties, lamins flowing) et B-type of (liquid-like, with combination viscous Swift a and as (spring-like) 2013; characterized al., elastic been et al., has Harada response 2C; et mechanical By (Fig. properties Shin 2007). nuclear 2014; to al., thus lamins A-type is et of B-type contributions it and characteristic Pajerowski compositions, the approximate lamina 2005; to different possible al., with nuclei et examining pressure be Dahl under can deformation which 2A,B; of nucleus, (Fig. rate the the detailed measuring of by properties the investigated mechanical enabled the of have study experiments aspiration Micropipette mechanical nucleus the the on of composition properties lamina of influence The motnl,dsiea paetrl nrifrigthe reinforcing in role apparent an despite Importantly, aioahe r aiyo iessta r asdby caused are that diseases of family a are Laminopathies ora fCl cec 21)17 0531 doi:10.1242/jcs.149203 3005–3015 127, (2014) Science Cell of Journal 3007

Journal of Cell Science dfrainrsos ie,tetmsaeoe hc h ula hp eom ne oc.Nce ihgetrqatte fAtp aisrelati The lamins (C) de A-type 2013b). lamin-A. together of al., of which quantities et expression properties, greater (Swift high with (flowing) stress with Nuclei viscous under force. those and slowly under than (spring-like) deforms more compliant elastic shape deform more of nuclear to be combination the found to which a were found over as lamins timescale were considered the (LMNA) be time’, lamin-A can response of lamina ‘deformation expression the low of with properties nuclei mechanical seconds, of order the N ehlto sa pgntcmcaimb hc gene which 2011). by al., mechanism et epigenetic (Eden study an the is in methylation recorded of DNA half-life half- the protein and showed of line proteins be cell to cancer all lamin lung A-type for human a average in proteins cellular the (Schwanha transcripts than higher slightly around and be – to mass the protein of cellular copies of 200 0.7% about for accounting COMMENTARY 3008 that showed the 10 of mouse around study are in recent is there that A transcriptome finding feedback. and a regulatory 2013b), proteome tight al., are a et lamins of have A-type (Swift suggestive We of tissue levels 3A. in protein Fig. correlated and in highly transcript summarized the are that regulated shown cells. be individual can of level lamin-C local the at of act mechanisms ligaments; have that to (for regulation and beneficial it lamin meniscus making straining tissues, 2012), cartilage, Neu, inhomogeneous and articular bulk Chan human cause within in to can Even example response in surroundings. loading vary levels their mechanical protein the that from by note to determined feedback organ, important or being also tissue given to is a it addition make to In required physical programming tissue. the epigenetic with the nucleus of the to of demands regulated properties closely mechanical are the lamins match that development posited has discussion brain Earlier regulation in lamin of 2011). Mechanisms defects al., et to Kim 2011; due their al., et being with (Coffinier embryogenesis, and death lamin-B1 through with eventual progress models constitutive ablation mouse apparently lamins, lamin-B2 the heart al., B-type Despite from et of 1999). Kubben die 2012; expression al., al., et typically et Sullivan (Jahn and birth 2011; tissue after weeks defects connective several display failure and knockout lamin muscle A-type in of al., et models Sandre-Giovannoli Charcot-Marie-Tooth Mouse (De – 2002). system muscle nervous exceptions heart, the are bone, affects there disorder (i.e. However, lamin fat). nuclear and dominant the are lamins micropipet the of function for a (achieved, as compositions timescales lamina deformation altered of experimentally range with a nuclei over of calculated range ( be deformation a can of in Compliance extent the stiffness) construct). diameter, of fusion inverse GFP–lamin-A nucleus. the a the ‘softness’, overexpressing in of lamin measure of a role (effectively mechanical The 2. Fig. h aymcaim ywihtelvl flmnAand lamin-A of levels the which by mechanisms many The , asfrtepoenand protein the for days 4 A Lamin-A increasesnuclearviscosity Nucleus (GFP-lamin-A) LMNA L , 7 usre l,21) esrmnsmd on made Measurements 2011). al., et ¨usser 2hus ogl ntemdl ftespan the of middle the in roughly hours, 12 oiso -yelmnpoen e el– cell per proteins lamin A-type of copies Micropipette Δ rncit aflf ntecl sreported is cell the in Half-life transcript. P L n h ple rsue( pressure applied the and ) ,

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Nuclear compliance B A eomtosapidb irppteaprto eeue oqatf ula compliance nuclear quantify to used were aspiration micropipette by applied Deformations (A) Time (seconds) D P .()We osatdfrigpesr a eiee ymcoiet vrtmsae on timescales over micropipette by delivered was pressure deforming constant a When (B) ). bevdi h ehlto fthe of methylation the in observed ciiycnb euae,bti a icutda h foremost the as discounted was it but regulated, be can activity ta. 01 uhe l,19)hv enreported. been have 1997) al., (Kolb et assembly Pugh lamina 2011; and 2005), al., properties, al., et physical et both (Broers mobility in as lamin- differences such of although Little roles lamin-C, 2013). functional and al., different A et about Jung understood 2012; currently al., is micro-RNA et (Jung the spliceoform brain, lamin-A in and, 2013b), lamin-C MIR-9 al., the et lamin-C expresses (Swift truncated mRNA preferentially spliceoform and resulting generally the lamin-A tissue with the Soft 2013b), forms. give al., to 2001; et al., spliced Swift et alternatively proteins; Olins 2013; 2004b; al., family al., et et RXR Shin Okumura the 2004a; and of al., (RAR et factors Okumura transcription family by controlled be retinoic-acid to reported A-type with been patients of 2007). from has al., levels tissues et in different (Cortese or disorders 2013b) express laminopathic al., to et (Swift known protein lines lamin cell of range controlling of means 06,adide,lmn r ihypopoyae during phosphorylated highly al., are et lamins (Omary indeed, upregulated. proteins is and filament and is sites 2006), intermediate conformation a solubility, of four as protein the recognized organization modulating at is for lamin mechanism phosphorylation substrate. key of stiff A-type the substrate on extent that decreased stiff of but the on domain), Furthermore, maintained Ig-like quantity globular is the total lamin are of 3B, A-type that the (Fig. substrate (specifically, of that smooth revealed soft and fold analyses taut native proteomic on are appear showed Accompanying nuclei and panel). the cells MSCs fibers left substrate, stress cultured stiff of by on the flattened brain whereas, envelopes relaxed, of either and nuclear Images wrinkled of 2010b; the 2013b). ECM al., et al., that the (Buxboim with kPa) et mimic (40 bone Swift to pre-calcified hydrogels or set kPa) (0.3 were polyacrylamide that stiffnesses type-I-collagen-coated cultured were (MSCs) in cells on regulated stem mesenchymal actively it’ stress, are to proteins lose response lamin or how it understand ‘use better – To lamin of regulation Stress-responsive HighLMNA Low LMNA LMNA Medium ora fCl cec 21)17 0531 doi:10.1242/jcs.149203 3005–3015 127, (2014) Science Cell of Journal pcfclytresaddatvtstemN fthe of mRNA the deactivates and targets specifically Soft Stiff LMNA response time ees–n ossetcagswere changes consistent no – levels C Deformation Lamin-B (elastic) LMNA (viscous) Lamin-A rmtrete na in either promoter LMNA Elasticity Viscosity transcription xml,by example, et B-type to ve iethe fine te

Journal of Cell Science COMMENTARY uei rls t yai,weeynnesnilAtp ai is a lamin to A-type non-essential point whereby hence dynamic, it’ observations lose These or it 2013). ‘use prelamin-A al., in et S404 (Bertacchini of observed (as phosphorylation mobile turnover Akt-mediated to more susceptible following more phosphorylated, A- lamin hypothesize, extensively we substrate, so, more soft A-type and On are lamina. decrease lamins the with type strengthening to process, so this and acting of in solubility converse phosphorylation lamina the observe we Blobel, is decreased response the stress the and substrate-induced Thus, of (Gerace 1990). to McKeon, separation and disassembly Heald chromosomal 1980; the tensio for prot of coiled-coil driving direction multimeric preparation the of indicate , example Arrowheads another mechanism. suscept is the normal less experiment metalloproteinase for be This matrix generality to 2010). a some al., shown with suggesting et been treatment stress, (Flynn have subsequent to intact tension stretching, subjected remain mob under localized when tension and fibrils to solubility under regulated collagen subjected the are enzymatically Right: is reduces that being 2013b). phosphorylation collagen ten fibrils by al., of greater fibrillar the altered level et of of is but lower (Swift film suggestive collagen A with lamina a appearance, 2013b). interaction the when stretched because al., of be et digestion; smooth might ‘stress-strengthening’ (Swift enzymatic a this 201 th filaments a that have Left: al., protein hypothesize drives substrate (B) lamin we et thus 2011). stiff – of (Swift al., and tension on organization et tension under the cells Vos phosphorylated under in (De in less suppressed changes factors is those transcription is induced lamin whereas of A-type phosphorylation wrinkled, ingress that and ha shown allow are lamin, have pathways that substrate We defects A-type stress-dependent soft the of Further on transient in turnover. Ig-domain (following have cultured mobile protein the to lamin-A MSCs remains enzymatic of shown Mature protein been precede unfolding 2012). some have al., might causes although nuclei et and nucleus Laminopathic lamina, (Jung solubility, the nuclear spl miRNA increased on the alternatively through to stress into is suppressed leads reported; assemble is (gray) Phosphorylation form red) transcript 2008). lamin-A in The the al., shown 2001). brain, (both et al., as lamin-C et such and Olins tissues, processing) 2004a; some translational al., In et forms. (Okumura lamin-C stress. factors and lamin-A of retinoic-acid-binding by function promoted a is as transcription regulation Protein 3. Fig. A B Regulationof A-type laminproteinfeedsbackontranscription Tension-dependent regulationofproteinlevels relaxednuclei Soft substrate LMNA Nucleus rnldlmn Smoothlamina Wrinkled lamina LMNA binding factors Retinoic-acid- promoter lamin A-type X Chromatin interaction tensenuclei Stiff substrate Ig domain with lamina lamin B-type Transcription phospho-lamin Nucleoplasmic small moleculeimport Transcription factorand A ceai hwn h atr htcnrglt h eeso -yelmni h cell. the in lamin A-type of levels the regulate can that factors the showing Schematic (A) Tail Tension protein unfolding Stress-induced LMNC LMNA h omr hne ntepopoyaino of microtubules phosphorylation of assembly the the affect in (MAPs) proteins changes of associated example former, an external As where state. the phosphorylation contrast, in by changes drive or, stresses phosphorylation by regulated are lamin Swift which in circuit by gene 2013b). mechanism (see al., lamin-promoting transcription et feedback own the its been a promotes receptor of protein to has acid pointing translocation lamins retinoic nucleus, A-type the factor of drive transcription level to The reported degraded. eventually hr r ubro ae nteltrtr hr elmechanics cell where literature the in cases of number a are There used toapplystrain Probe tips ora fCl cec 21)17 0531 doi:10.1242/jcs.149203 3005–3015 127, (2014) Science Cell of Journal Tension Assembly membrane cracking Stress-induced iN miRNA (under stress) Disassembly (relaxed) Solubility-regulated by phosphorylation Lamin-C Lamin-A filaments Coiled-coil Time c Turnover of unstressed Degradation RR)t the to (RARG) filaments cdt iers to rise give to iced erdsthe degrades LMNA i assembly ein ebeen ve lt flamin of ility uliof nuclei e n. beto ible 3b). stress- (Shimi 3009 sion. post-

Journal of Cell Science usrt tfns n cst euaecl otatlt Ra tal., et non-muscle (Raab contractility cell of regulate to phosphorylation acts which and stiffness the signaling substrate by BCAR1), and biochemical (encoded 2006), as myosin-IIa al., into known et stretching (Sawada (also substrate mechanical Cas p130Cas transduces the protein, of both domain phosphorylation include case extension-dependent second (Matenia the cytoskeleton the of the Instances in 2009). Mandelkow, roles and structural important have that COMMENTARY BN;Mne eOae l,20) lamina-associated lamin-B 2009), and al., ERBB2IP) 3010 as et known also Oca (LAP2, de 2 nuclear factor the polypeptide 2010), with Montes barrier-to-autointegration interact al., that , include (BANF; et proteins including of (Simon interactions range actin membrane, a These like to directly’’. binding proteins, and structural both) to (or B- all binding or ‘‘almost A- lamins review: to their bind type proteins in membrane] Berk nuclear 2010), and [inner Foisner, characterized Wilson and by Wilson 2010; emphasized Berk, as and (Wilson the nucleus the on lamina nuclear the envelope. inner to nuclear bind of the turn, of in family inside these, and SUN-domain-containing proteins and nesprins the membrane network; kinesin microtubule to with the interact to bind tether also turn, to can in complexes nuclear Nesprins which, dynein , -3. the protein to desmosome to binds intermediate the The and to binds bind nesprin-2, F-actin filaments 2013). and nesprin-1 proteins; cytoplasmic components Huck, between structural envelope intermediary nucleoskeleton and nuclear an of as and Watt (Puklin- (linker acts cytoskeleton) complex actin 2009; and focal LINC cytoplasmic named Sheetz, and to appropriately integrins and bind by that Faucher mediated complexes are adhesion 2002). cytoplasmic Fuchs, interactions and and with (Jamora actin, Cell–ECM keratin interact to as such that tether through filaments, intermediate that complexes cytoskeleton junctions desmosome the adherens through to and 1A; link junctions (Fig. al., tight interactions et nucleus Sosa 2011; Cell–cell 2013; Wilson, its Worman, and 2013). Simon and 2013; Gundersen of Kutay, and e.g. Rothballer reviews, machinery that recent cell linkages in transcriptional a protein discussed of surroundings of the the system from a into signals of in transmission component the key allows a is Lamin ECM of downstream lamin – and nucleus in the to remodeled 2009). 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have to Traub, lamins bind the and indeed, Shoeman to and shown 2007), Krohne, been lamina and the (Wagner also proteins heterochromaticform silenced with lamin-binding its in Many particularly in interact chromatin, 2009). with interact Oct-1, al., role et some the as its (Malhas Furthermore, directly of such 2013). and translocation al., factors, et 2014), the transcription (Ho on al., MKL1 factor effect et tension transcription its has to (Guilluy mediating response through emerin in nesprin-1 in mechanosensing nuclei these, role to isolated of Of its applied stiffness for 2013). the in interest al., changes recent et considerable Solovei attracted (LBR; receptor rmotietecl r elce natrtosi protein in alterations in reflected are cell the and outside conformation from concentration, factors. local transcription or cofactors through binding, of delivered locations modification be spatial in can precise specificity changes at biochemical Perhaps nucleus. to genes the mechanical individual within from activate converted to be signals this can microscopic from without – acting missing perturbations which coherence and by forces is mechanism – the inputs What of blunt understanding to 1997). an exterior is al., cell however, picture, the et from (Maniotis transmitted chromatin be can through linkage deformations physical which continuous a completes thus interactions Fnne l,20;Iinoe l,21;Klnwk ta. 03,as 2013), al., et pressure Kalinowski osmotic 2013; 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Journal of Cell Science ubi,A,Iaosa .L n ice,D E. D. Discher, D. and R. L. Goldman, I. and Ivanovska, E. A., A. Buxboim, Goldman, A., S. Adam, V., and Butin-Israeli, J. Endert, J., H. Worman, C., Ostlund, H., J. H. Kuijpers, V., L. J. Broers, V. C. Bouten, J., Endert, H., J. H. Kuijpers, G., A. E. Peeters, V., L. J. Broers, epnet ellrsrs scasclytogto ntrso how essentially of terms are in The of we 2012). thought al., classically the driving – et is (Zuela stress by fate meet cellular response to indirectly, stress cell In response in cell to or to role a directly is the migration. regard lamin allocating either lamins with of – cell changes of properties tissue broader functions a regulate mechanical key of the lamina, also demands the that the of and of ensure one properties fate that protective understanding cell the determine influence they how COMMENTARY res .L . ahes .M,Kipr,H .H,Set,F,vnden van F., Smedts, H., J. H. Kuijpers, M., B. Machiels, V., L. J. Broers, Be S., Varnous, R., M. Barletta, Di G., Bonne, Marin, L., Mediani, F., Gibellini, M., Guida, V., Cenni, F., Beretti, J., Bertacchini, Diemen, Delis-van H., Bril, G., E. Berg, den van A., J. R. Fijneman, T., J. E. Belt, Canoll, and S. S. Rosenfeld, R., Vallee, P., Monzo, C., M. Assanah, C., Beadle, H. Wen, and S. R. Balaban, S., Ding, H., A. Aletras, months. 12 References after release for PMC and in Science Deposited Nano Interface). Engineering; Nano/Bio research and Engineering; U.S. Pennsylvania’s Science the of Research Health, University (Materials of the centers Institutes and National Foundation U.S. Science the National from support appreciate We Funding interests. competing no declare authors The interests comments. Competing helpful Stephanie for and Pennsylvania Ivanovska L. of Irena University Dingal, the P. at Dave C. Majkut P. colleagues our thank We Acknowledgements play. features to biophysics stress role nuclear structural that important understanding which apparent of an is has fully in it regulation Nonetheless, from way cell. the the within way the affect long and pathways response mechanisms a still protection 2012). Noble, cellular are and molecular we (Silver the However, of expression protein the heat-shock induce chaperone mechanical to the ECM, sufficient as the is from Just the stretching inputs 2010). mechanical al., involve to structural et responds drive lamina that (Toivola that proteins those responses filament and intermediate proteins cellular heat-shock of of between highlighted loss expression review associated recent similarities Another with mechanical 2013b). the unfolding high but al., et protein 2011), in (Swift cause al., result function also et otherwise (Hartl can can proteins stress which unfolded of shock, levels heat mitigate cells yokltlfre n hsc ftences o epyd el fe’outside ‘feel’ cells do deeply how nucleus: in? the and of physics and forces cytoskeletal disease. and functions lamin . lamin nuclear internal of loss 304 as well as instability S. C. F. Ramaekers, S. laminopathies. C. F. of development Ramaekers, nucleo- the Genet. and defective Mol. for by T. caused implications P. is integrity: F. cells cytoskeletal LMNA-/- Baaijens, in J., stiffness mechanical W. Decreased C. Oomens, C., 505-517. r ifrnilyepesdi omlhmntissues. human normal in expressed C. differentially F. are Ramaekers, and Y. Raymond, al. dominant R., Kieboom, et autosomal A. cause A/C J. lamin Urtizberea, F., encoding dystrophy. Gary, gene muscular R., Emery-Dreifuss the C. in Greenberg, F., (1999). Muntoni, L., Merlini, expression. gene Lmna and al. degradation et J. A G. prelamin Lattanzi, both A., regulates Pol, PKB de M., N. Maraldi, O., Belie S., E. recurrence. Klerk, disease with associated Lange-de is cancer de al. colon F., et H. B. Essen, H. van Stockmann, M., Tijssen, M., P. 3357-3368. P. MRI. functional 247-252. cardiac in echoes stimulated with encoding 20) h oeo ysnI ngim naino h brain. the of invasion glioma in II myosin of role The (2008). 27 582-592. , 2145-2155. , .Cl Sci. Cell J. 13 2567-2580. , 123 20) ohlmnAadlmnCmttoscuelamina cause mutations C lamin and A lamin Both (2005). 297-308. , 21) oso ai / xrsini tg IadIII and II stage in expression A/C lamin of Loss (2011). a.Genet. Nat. rnsGenet. Trends cn,H . amua .H., E. Hammouda, M., H. ´cane, 21) h rti iaeAkt/ kinase protein The (2013). 19) ES:displacement DENSE: (1999). 21 u.J Cancer J. Eur. 19) -adBtp lamins B-type and A- (1997). 285-288. , itce.Cl Biol. Cell Histochem. 21a.Mti elasticity, Matrix (2010a). 28 464-471. , .Mg.Reson. Magn. J. o.Bo.Cell Biol. Mol. 47 x.Cl Res. Cell Exp. 1837-1845. , n .A., J. ¨n, FASEB (2012). (2004). Hum. 107 137 19 , , , nlr .J,Sn . wee,H .adDshr .E. D. Discher, and L. H. Sweeney, S., Sen, J., A. Engler, Bo S., Sen, A., M. Griffin, J., A. Engler, dn . eaZtrk,N,Isea . oe,A,Dkl . ao,T., Danon, E., Dekel, A., Cohen, I., Issaeva, N., Geva-Zatorsky, E., Eden, ofne,C,Jn,H . ouoi . hn,S,T,Y,Bre,R . 2nd, H., R. Barnes, Y., Tu, S., Chang, C., Nobumori, J., H. Jung, C., Coffinier, P. C. Neu, and D. D. C. Chan, Cordoncardo, and G. Blobel, J., H. Worman, N., Chaudhary, G., W. Cance, ulk . acif,A n o,V C. V. Mow, and A. Ratcliffe, F., Guilak, cese-aln .A,Brmn,J . aa,Z n pco,D L. D. Spector, and Z. Lazar, M., H., J. Cordenonsi, Bergmann, S., A., M. Giulitti, Eckersley-Maslin, E., Enzo, M., Aragona, L., Morsut, S., Dupont, T. Misteli, and A. T. Dittmer, ubi,A,Rjgpl . rw,A .X n ice,D E. D. Discher, and X. E. A. Brown, K., Rajagopal, A., Buxboim, uln . ai,L,Bast . elmn . aa .B,Tlot W., Talhout, B., M. Faza, W., Meuleman, E., Brasset, L., Pagie, L., Guelen, G. Blobel, P. and Matsudaira, L. L., Gerace, Mahadevan, C., F. MacKintosh, H., J. Shin, L., M. Gardel, M. J. H. C. Frost, Hutchison, and G. W. Bickmore, R. and P. Wilson, Fraser, A., S. Przyborski, R., C. Foster, W. J. Ruberti, and A. C. Dimarzio, M., Liles, N., Saeidi, P., A. Bhole, P., B. Flynn, aisn .M n amrig J. Lammerding, and M. P. Davidson, E. D. Discher, and D. J. Pajerowski, J., A. 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Mayo, L., Cohen, 53-60. nlmnB n ai 2cuenuoeeomna eet n distinct and defects neurodevelopmental cause B2 . lamin in abnormalities and al. shape et nuclear B1 K. Reue, lamin L., Vergnes, in J., P. Jong, de Y., Yoshinaga, human exogenous neoplastic under resonance. and measured normal strains in lamins nuclear the tissues. of Expression (1992). oa isesri natclrcriae ofclmcocp study. microscopy confocal a cartilage: articular Res. in strain tissue local ai / sepesdi lrptn os mroi tmcells. stem embryonic mouse pluripotent in expressed is A/C Lamin al. et S. Bicciato, M., mechanotransduction. Forcato, in J., YAP/TAZ Digabel, Le F., Zanconato, 222. epyclsfe:mtosfrti gels. thin for methods feel: cells deeply raiaino ua hoooe eeldb apn fncerlamina nuclear al. of et W. mapping Laat, by de revealed L., interactions. Wessels, human A., of Klein, organization de H., B. Eussen, mitosis. during depolymerized A. networks. D. Weitz, and 219 regulation. gene for potential biomarkers. cancer as against Lamins fibrils 8 metalloproteinase collagen matrix collagenase reconstituted mammalian (MMP-8). stabilizes by degradation strain enzymatic Mechanical (2010). hooyo sltdnce ihdfrainmpigo ula substructures. nuclear of mapping deformation with J. Biophys. nuclei isolated of rheology cells. mammalian in regulation gene and lipodystrophy. partial familial with patients T. fate Brune, cell and stem epidermal regulate to microenvironment the decisions. M. from F. cues Watt, physical and S. T. W. otesifeso hi substrate. their of stiffness the to lamins. Nuclear 4175-4186. rpriso h elnucleus. cell the of al. properties dilated et of causes U. as Girolami, gene A/C De lamin the S., disease. conduction-system of and Spudich, cardiomyopathy domain rod Jr, the J., in mutations Missense H. Vidaillet, J., Atherton, adr,E .M,Vrtatn .L,vnSene,M .M,Mrei,C L. C. Marcelis, M., A. M. Steensel, van al. L., et V. M. 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Journal of Cell Science ob . as,K,Hrt . ei .adHrmn,H. Herrmann, and U. Aebi, M., Hergt, K., Maass, T., Kolb, li,E . i,L,Ktaal,D,Csann,P,Bfed .J,X,T., Xu, J., F. Byfield, P., Castagnino, D., Kothapalli, L., Yin, A., H., Janssen, E. S., Klein, S. Vries, de S., Boyle, H., Ortabozkoyun, L., Y. Pagie, J., Zheng, Kind, and X. Zheng, N., Y., Gaiano, M., Kim, C. Fan, H., Hao, M., Cheng, K., McDole, A., A. Sharov, Y., Kim, aiosi . i,Z,Cfe,K,Kdl,R,Belr .J,Lo G. J., L. M. Buehler, Fong, R., and Kodali, K., G. Coffey, S. Z., Young, Qin, A., H., Kalinowski, S. Yang, M., J. Lee, J., H. Jung, ug .J,Cfiir . he . egex .P,Dve,B .J,Yn,S H., S. Yang, J., S. B. Davies, P., A. Beigneux, Y., Choe, C., Coffinier, J., H. Jung, Hu and A. D. Jans, E. Fuchs, and C. Jamora, eee .A,Co . uf .W n nesn .M. C. Anderson, and W. M. Huff, H., Cao, A., R. Hegele, F. McKeon, and R. Heald, A. R. Brown, and V. Mudera, E., Hadjipanayi, an . crm,S,Schno S., Schramm, D., Jahn, Iyer,K.V.,Maharana,S.,Gupta,S.,Libchaber,A.,Tlusty,T.and ajpny,E,Mdr,V n rw,R A. R. Brown, and V. Mudera, E., Hadjipanayi, J. H. Worman, and G. G. R., Gundersen, Superfine, L., Sharek, L., Landeghem, Van D., L. Osborne, C., Guilluy, COMMENTARY 3014 P. C. Neu, and I. A. Veress, G., Shannon, T., J. Henderson, M. Hayer-Hartl, and A. A., Bracher, U., Athirasala, F. R., Hartl, K. Spinler, J.-W., Shin, J., Irianto, J., Swift, T., Harada, o .Y,Jaok .E,Vriie,M .adLmedn,J. Lammerding, and K. M. Vartiainen, E., D. Jaalouk, Y., C. Ho, J. Lammerding, and Y. C. Ho, U. Aebi, and P. Burkhard, V., S. Strelkov, H., Herrmann, voi,S,Bal,C,Ntcwl,S,Mse,S . wno,K . oo .N., L. Toro, R., K. Swanson, C., S. Massey, S., Noticewala, J. C., Beadle, S., Ivkovic, Lammerding, and P. E. D. Isermann, Discher, M., M. Knight, D., G. McPhail, P., R. Martins, M. J., Swift, Snyder, J., and Irianto, G. Mor, K., Haines, I., Pozdnyakova, E., M. Hudson, ai omhmdmr n oxs nhge ope om ohi the in cells. both human forms cultured complex of higher lamina in the coexist in 425-433. and and fraction homodimers nucleoplasmic form C lamin 2246-2253. yl oto ypyilgclmti lsiiyadi iotsu stiffening. tissue K. vivo R. in and Assoian, elasticity and matrix Biol. A. physiological P. by Janmey, control cycle E., Hawthorne, B. I., Steensel, Levental, van and interactions. A. lamina W. genome-nuclear Bickmore, of D., dynamics Single-cell L. Nolen, M., Amendola, lamins. all lacking cells stem embryonic mouse cells. stem embryonic by not Y. but Zheng, organogenesis and H. S. M. Ko, oanta rmtsfrey-eitdmmrn association. membrane farnesyl-mediated regulation. promotes that and domain N. function K. into Dahl, insights new - brain the Neurobiol. in lamins Nuclear rlmnAbtntlmnCb i-,abanseii microRNA. brain-specific a USA miR-9, al. by Sci. et C J. lamin S. not Pleasure, but T., A Sun, prelamin J., Hong, 2nd, H., R. Barnes, phosphorylation. of role central cytoskeleton. uaini ata ioytoh soitdwt eue lsaleptin plasma reduced with associated lipodystrophy partial concentration. in mitosis. in disassembly lamina nuclear prevent that 1376-1389. h ma--mueln:ipiain o h nesadn flaminopathies. of understanding the for implications line: mouse Nucleus -/- Lmna the Schu chromosomes. of organization spatial and ONE transcription PLoS global between link the V. G. Shivashankar, motogens. multiple of presence Cell the Biol. in Mol. invasion glioma blocks effectively II myosin ula ai tfns sabrirt Dmgain u otescnlimit can softness but proteostasis. migration, and 3D folding protein to barrier E. D. a Discher, and is L. survival. stiffness I. Ivanovska, lamin P., D. Nuclear C. P. Dingal, R., Diegmiller, stiffness. directional graded with 66 matrix collagen a stiffness. 3D: matrix scaffold collagen Med. on Regen. proliferation nucleus. the in 381. pathway mechanotransduction K. a Burridge, reveal and R. Garcia-Mata, 2093. plasticity. and architecture 119 cell of determinants single primary in filaments: synthesis RNA tissue. native and within distributions embedded strain cells intranuclear of measurement rsik .R,Cnl,P n oefl,S S. S. Rosenfeld, and P. Canoll, R., A. Bresnick, disease. and health in mechanotransduction . in condensation A. D. Lee, high- and using cancer ovarian in microarrays. proteins protein expressed density differentially of Identification dynamics. actin modulating by activity 497 MKL1-SRF regulate emerin and C 121-128. , 1772-1783. , 507-511. , z . eaet,R n lhie,M. Alsheimer, and R. Benavente, W., tz, ¨ 19 1511-1518. , 3 .Cl Biol. Cell J. 109 463-474. , 47 7 21) acu assacnomtoa hnei ai tail A lamin in change conformational a causes Calcium (2013). e46628. , E423-E431. , 290-301. , 3 a.Cl Biol. Cell Nat. 23 .Ci.Edcio.Metab. Endocrinol. Clin. 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Dabauvalle, G., Krohne, uh .E,Cae,P . ae .B,Ryod .adQiln .A. R. Quinlan, and Y. Raymond, B., E. Lane, J., P. Coates, E., G. Pugh, Mosca, R., Douglas, K., R. Jaiswal, C., S. Beck, M., A. Mackay, F., M. Pittenger, ab . wf,J,Dna,P .D . hh . hn .W n ice,D E. D. Discher, and J.-W. Shin, P., Shah, P., D. C. P. Dingal, J., Swift, M., P.Raab, M. Sheetz, and E. Puklin-Faucher, E. D. Discher, and J. P. Sammak, L., F. Zhong, N., K. Dahl, Franklin, D., L., J. C. Pajerowski, Fisher, W., G. Wylde, R., C. McClain, K., Franze, S., Pagliara, mr,M . u .O,To .Z,Tioa .M n io J. Liao, and M. D. Toivola, Z., G. Tao, O., N. Ku, B., M. Omary, A., A. Noegel, H., Zentgraf, H., Herrmann, M., Zwerger, V., T. Hoang, L., A. Olins, Olins, and D. Doenecke, M., Kratzmeier, P., Lichter, H., Herrmann, L., A. Olins, N. Nakajima, and Y. Hosoe, K., Okumura, kmr,K,Hse .adNkjm,N. Nakajima, and Y. Hosoe, K., Okumura, enr .F,Sik . pebre,H .adNg,E A. E. Nigg, and M. G. H. S. Eppenberger, Young, R., L., Stick, F., C. C. Stewart, Lehner, K., Reue, Y., J. Ji, G., L. Fong, J., Lammerding, ahs .N,Le .F n ax .J. D. Vaux, and F. C. Lee, E. N., D. A. Discher, and Malhas, A. Liu, C., Krieger, J., Swift, T., Idema, S., I., Majkut, Duband-Goulet, T., C. Freberg, E., Delbarre, R., A. Oldenburg, E., Lund, L. Y. Wang, and M. Lude Dembo, B., H. Wang, M., C. Lo, aits .J,Ce,C .adIge,D E. D. Ingber, and S. C. Chen, J., A. Maniotis, cet,R,Prn,D . esn .M,Barrj,K n hn .S. C. Chen, and K. Bhadriraju, M., C. Nelson, M., D. Pirone, R., McBeath, M. E. Mandelkow, and D. Matenia, upy .J,Pec,J,d asekr . ie,J,Nbet . de D., Neblett, J., Libes, C., Caestecker, de J., Pierce, J., A. L. K. Murphy, Wilson, and N. R. Cole, M., Gucek, J., C. Shoemaker, R., Oca, de Montes M., Kellis, L., Pagie, B., J. Beaudry, J., Kind, D., Peric-Hupkes, Perry, W., M., Meuleman, C. A. Smith, V., Sachdev, S., Clauss, B., L. Gordon, A., M. 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Journal of Cell Science oa .A,Kty .adShat,T U. T. Schwartz, and U. Kutay, A., B. Sosa, M., Zwerger, S., Krebs, S., C. Schmidt, K., Thanisch, S., A. Wang, I., Solovei, L. K. Wilson, and S. M. L. Zastrow, N., K. D. Simon, Wilson, and N. D. Simon, pcmn .A,Gr,A,D,F,Bnet . el,R,Aigu . alr .I., S. Taylor, E., Arioglu, R., Veile, L., Bennett, F., Du, A., Garg, A., R. Speckman, aaa . aaa . ui-hlr .J,Cenasaa . aa,R., Sakai, O., Cherniavskaya, J., B. Dubin-Thaler, M., Tamada, Y., Sawada, E., D. Olins, A., I. Eydelnant, L., W. Ung, M., Zwerger, E., D. Jaalouk, C., A. Rowat, U. Kutay, and A. Rothballer, Ro COMMENTARY ivr .T n ol,E G. E. Noble, and T. J. Silver, P. Traub, and L. R. Shoeman, Discher, and N. Mohandas, A., J. Chasis, J., Swift, R., K. Spinler, J.-W., E., Shin, A. Goldman, I., Solovei, G., C. Pack, S., Kojima, K., Pfleghaar, F., T., M. Shimi, Niermeijer, R., Evans, J., N. S. Jackson, J., D. Lloyd, S., Shackleton, Schwanha ulvn . saat-lad,D,Bat . ne,M,Ba,N,Nagashima, N., Bhat, M., Anver, H., Bhatt, D., Escalante-Alcalde, T., Sullivan, Stierle hvsakr .V. G. Shivashankar, e,R . atr . ee,K n son M. Osborn, and K. Weber, H., Sauter, A., R. ber, ¨ eunilytte eihrlhtrcrmtnadivreyregulate inversely complexes. and heterochromatin peripheral tether al. differentiation. et L. sequentially Peichl, R., Foisner, C D., Devys, V., T. Cohen, tail. A lamin the by bundling filament actin 264-272. and tails lamin B-type and networks’. of ‘network dynamic associated aiiswt aiilprillpdsrpy(ungnvrey eelrecurrent reveal A/C. lamin variety) of domain (Dunnigan C-terminal Genet. globular lipodystrophy the in partial mutations missense familial M. with A. families Bowcock, and M. Lovett, tesChaperones Stress vimentin. and proteins lamin nuclear purified cells. hematopoietic chromatin human in E. involved D. microdomains networks: al. transcription. et and lamin T. organization Cremer, M., nuclear Kinjo, K., B-type D. Shumaker, lipodystrophy. A., partial S. al. Adam, et in N. mutated P. is Durrington, S., A/C, Kumar, lamin G., Genet. encoding Brabant, LMNA, H., Schmidt, (2000). M., B. Singh, M. control. Selbach, expression and W. Chen, p130Cas. substrate kinase family Src P.the M. Sheetz, and S. Tanaka, passage to cells -type J. Lammerding, of constrictions. micron-scale and ability through A. the D. determines Weitz, composition H., envelope Herrmann, L., A. Olins, chromatin. distinction and A/C: cytoskeleton the lamins to lack envelope mouse the cells. of somatic system other versus hemopoietic and immune . twr,C .adBre B. Burke, and domain. L. binding C. DNA Stewart, a K., contains C and A lamins I. to Duband-Goulet, common and region C. J. terminal Courvalin, J., H. Worman, regulation. ,V,Cure . sln,C,Kim . inJsi,S,Hselp,P., Hossenlopp, S., Zinn-Justin, I., Krimm, C., Ostlund, J., Couprie, V., ´, 21) aisrglt eltafcigadlnaemtrto fadult of maturation lineage and trafficking cell regulate Lamins (2013). 66 24 usr . us,D,L,N,Dtmr . cuhad,J,Wl,J., Wolf, J., Schuchhardt, G., Dittmar, N., Li, D., Busse, B., ¨usser, 1192-1198. , 153-156. , nulRve fBiophysics of Review Annual ur pn tut Biol. Struct. Opin. Curr. 42 Cell 4819-4828. , 152 Nature 17 21) ehnsgaigt h elncesadgene and nucleus cell the to Mechanosignaling (2011). 1-9. , 584-598. , 473 .Cl Sci. Cell J. 21) h ies ucinlLNso h nuclear the of LINCs functional diverse The (2013). rc al cd c.USA Sci. Acad. Natl. Proc. 21) lblqatfcto fmmaingene mammalian of quantification Global (2011). 20) oc esn ymcaia xeso of extension mechanical by sensing Force (2006). 21) euaino uvvlgn hsp70. gene survival of Regulation (2012). 337-342. , ee Dev. Genes 19) h nvtoDAbnigpoete of properties DNA-binding vitro in The (1990). 20) uainladhpoyeaaye of analyses haplotype and Mutational (2000). 21) h ulokltna genome- a as nucleoskeleton The (2011). .Bo.Chem. Biol. J. 23 19) oso -yelmnexpression lamin A-type of Loss (1999). 285-291. , 95 40 587-598. , a.Rv o.Cl Biol. Cell Mol. Rev. Nat. Cell 21) tutrlisgt noLINC into insights Structural (2013). 361-378. , 22 .Bo.Chem. Biol. J. Chromosoma 3409-3421. , 21) ietatnbnigt A- to binding actin Direct (2010). 127 288 1015-1026. , 19) el ftecellular the of Cells (1990). 8610-8618. , 21) B n ai A/ lamin and LBR (2013). 110 20) h carboxyl- The (2003). 122 18892-18897. , 20) h -and A- The (2008). 265 415-429. , 21) Nuclear (2013). 9055-9061. , 12 m .Hum. J. Am. Nucleus 695-708. , Nat. Cell 1 , il,C . aakr,F .S,Bor,J .V,Hthsn .J n Neumann, and J. C. Hutchison, V., L. J. Broers, S., C. F. Ramaekers, M., C. Tilli, anr .adKon,G. Krohne, and H. N. K. Yang, Wagner, and I. A. King, L., Zhang, J., E. 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