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Contents lists available at ScienceDirect

Seminars in Cell & Developmental Biology

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amina-associated polypeptide (LAP)2� and nucleoplasmic lamins indult stem cell regulation and disease�

evin Gesson1, Sandra Vidak1, Roland Foisner ∗

ax F. Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, Dr. Bohr-Gasse 9, 1030 Vienna, Austria

r t i c l e i n f o

rticle history:vailable online xxx

eywords:dult stem cellsaminsaminopathies

a b s t r a c t

A-type lamins are components of the lamina network at the nuclear envelope, which mediates nuclearstiffness and anchors chromatin to the nuclear periphery. However, A-type lamins are also found inthe nuclear interior. Here we review the roles of the chromatin-associated, nucleoplasmic LEM protein,lamina-associated polypeptide 2� (LAP2�) in the regulation of A-type lamins in the nuclear interior. Thelamin A/C–LAP2� complex may be involved in the regulation of the retinoblastoma protein-mediatedpathway and other signaling pathways balancing proliferation and differentiation, and in the stabilization

uclear envelopeuclear envelopathiesrogeriaelf-renewal

of higher-order chromatin organization throughout the nucleus. Loss of LAP2� in mice leads to selectivedepletion of the nucleoplasmic A-type lamin pool, promotes the proliferative stem cell phenotype oftissue progenitor cells, and delays stem cell differentiation. These findings support the hypothesis thatLAP2� and nucleoplasmic lamins are regulators of adult stem cell function and tissue homeostasis. Finally,we discuss potential implications of this concept for defining the molecular disease mechanisms of lamin-linked diseases such as muscular dystrophy and premature aging syndromes.

© 2014 The Authors. Published by Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Interplay between A-type lamins and LAP2� . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Role of A-type lamins in disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.1. The mechanical model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2. The gene regulation model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.3. The stem cell model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Functions of nucleoplasmic lamin A/C–LAP2� complexes and their link to disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.1. Nucleoplasmic LAP2�–lamin A/C complexes in proliferation and differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.2. Lamins in stem cell regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.3. Impaired proliferation/differentiation pathways in laminopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5. Lamins in chromatin organization and implication for laminopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.1. The role of the nuclear lamina in chromatin organization and gene expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Please cite this article in press as: Gesson K, et al. Lamina-associated polypeand disease. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcd

5.2. A-type lamins and chromatin regulation . . . . . . . . . . . . . . . . . . . . . . . . . . .Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: ASC, (somatic) adult stem cell; BAF, barrier-to-autointegration factomery Dreifuss muscular dystrophy; ESC, embryonic stem cell; FPLD, familial partial liyndrome; iPS, induced pluripotent stem cell; LAD, lamina-associated domain; LAP, lamDPSC, muscle-derived stem/progenitor cells; MSC, mesenchymal stem cell; NE, nuclear

� This is an open-access article distributed under the terms of the Creative Commons Atny medium, provided the original author and source are credited.∗ Corresponding author at: Max F. Perutz Laboratories, Medical University Vienna, Dr. B

E-mail address: roland.foisner@meduniwien.ac.at (R. Foisner).1 These authors contributed equally.

084-9521/$ – see front matter © 2014 The Authors. Published by Elsevier Ltd. All rights ttp://dx.doi.org/10.1016/j.semcdb.2013.12.009

ptide (LAP)2� and nucleoplasmic lamins in adult stem cell regulationb.2013.12.009

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

r; Dam, DNA adenine methyltransferase; DCM, dilated cardiomyopathy; EDMD,podystrophy; INM, inner nuclear membrane; HGPS, Hutchinson–Gilford Progeria

ina-associated polypeptide; LEM, LAP2-Emerin-Man1; LRD, lamin rich domain; envelope; pRb, retinoblastoma protein.tribution License, which permits unrestricted use, distribution and reproduction in

ohr-Gasse 9, 1030 Vienna, Austria. Tel.: +43 1 427761680.

reserved.

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. Introduction

The nuclear lamina is a proteinaceous network in metazoanells that underlies the inner nuclear membrane (INM) and pro-ides mechanical stability for the nuclear envelope (NE) (Fig. 1)1–3]. It also fulfills a plethora of functions in chromatin orga-ization, gene expression and signaling during development andissue maintenance [4–10]. The lamina network is formed by type

intermediate filaments, the lamins [11–13], and a large num-er of lamin-binding proteins of the INM [14,15]. Structurally andunctionally, lamins are grouped into A- and B-type lamins [16].he main B-type lamins, lamin B1 and lamin B2 are encoded byMNB1 and LMNB2, respectively, and at least one B-type lamin isxpressed in most cells throughout development. A-type laminsre encoded by the LMNA gene, giving rise to two major isoforms,amin A and C, which are expressed later in development andn a differentiation-dependent manner [17]. Importantly, B-typeamins are processed post-translationally to yield a C-terminallyarnesylated mature protein that is tightly associated with the INMhrough its hydrophobic farnesyl group. In contrast, newly syn-hesized pre-lamin A is also farnesylated during processing, but in

final maturation step a C-terminal peptide, including the farne-yl group, is proteolytically cleaved, producing a non-farnesylatedature lamin A [18–20]. Therefore, unlike B-type lamins, A-type

amins are less tightly linked to the INM and the lamina and arelso found in a more mobile and dynamic pool throughout theucleoplasm [21–24]. However, the regulation and specific func-ions of this dynamic, nucleoplasmic pool of A-type lamins are stilloorly understood. Recent studies revealed evidence for excitingovel functions of this nucleoplasmic lamin pool in chromatin orga-ization, cell signaling and cell cycle control in adult tissue stemells (ASCs). In this review we discuss the potential functions ofucleoplasmic A-type lamins in fine-tuning the balance betweenroliferation and differentiation of ASCs, which is of crucial impor-ance for tissue homeostasis. We also discuss how nucleoplasmic-type lamins may affect the regulation of stem cell activity andow these functions may be altered in lamin-linked diseases.

. Interplay between A-type lamins and LAP2�

Lamina-associated polypeptide 2 � (LAP2�) is one of six spliceariants of the mammalian LAP2 gene (originally termed TMPO)25–28]. All LAP2 isoforms share the first 187 N-terminal residues29] harboring the LAP2-Emerin-MAN1 (LEM)-domain [30], which

ediates interaction with DNA in a sequence-independent man-er via the adaptor protein barrier-to-autointegration factor (BAF)31]. The common N-terminal LAP2 domain also contains a LEM-ike motif enabling direct interaction with DNA [30,31]. Thus, allAP2 proteins interact with chromatin by several mechanisms. The-terminal domain of LAP2� differs considerably from that of thether LAP2 isoforms. Whereas most LAP2 isoforms, such as LAP2�,re stably anchored in the INM via a C-terminal transmembraneomain, LAP2� is a non-membrane protein uniformly distributedhroughout the nucleoplasm [32]. Furthermore, whereas the LAP2

embrane proteins primarily bind B-type lamins at the nuclearamina [33], LAP2�’s unique C-terminal tail mediates exclusiveinding to A-type lamins [22,24] and contains an additional chro-osome association domain [34,35], as well as an interaction site

or the cell cycle and differentiation regulator, retinoblastoma pro-ein (pRb) [36,37].

The specific interaction of A-type lamins and LAP2� haseen extensively studied by several means, including co-

Please cite this article in press as: Gesson K, et al. Lamina-associated polypeand disease. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcd

mmunoprecipitation, cell cycle-dependent co-localization analy-es and a proximity based biotin ligase assay in mammalian cells,s well as by in vitro solid phase overlay and pull-down experi-ents [22,32,38,39]. These studies revealed direct interaction of

PRESSpmental Biology xxx (2014) xxx– xxx

lamins A/C and LAP2� via their C-terminal tails [22] and a dynamicassociation of the proteins during the cell cycle. The nucleoplas-mic lamin A/C–LAP2� complexes exist in G1 and early S-phase ofproliferating cells but are absent during mitosis [32,40]. Intrigu-ingly, LAP2� appears to be a crucial factor for the regulation andstabilization of the nucleoplasmic pool of lamin A/C and its local-ization in the nuclear interior (Fig. 1). In cells and epithelial tissuesderived from LAP2�-deficient mice, A-type lamins localize exclu-sively to the nuclear lamina and are absent from the nuclearinterior. Re-expression of full length LAP2�, but not of a laminbinding-defective LAP2� mutant, into LAP2�-deficient cells res-cues the nucleoplasmic pool of lamin A/C [24]. Furthermore, lossof the nucleoplasmic pool of A-type lamins during myoblast differ-entiation correlates with the downregulation of LAP2� [41].

Therefore, LAP2� is a master regulator of the nucleoplasmiclamin A/C pool, but the mechanisms by which LAP2� affects nucle-oplasmic lamins remain elusive. In G1 phase of the cell cycle,nucleoplasmic A-type lamins may originate from lamin complexesdisassembled in the preceding mitosis, or may represent newlysynthesized pre-lamin A, which may interact with LAP2� in thenucleoplasm only transiently, before they assemble into the nuclearlamina. The most intriguing scenario, however, is that A-typelamins are dynamically exchanged between the peripheral and thenucleopasmic pool, depending on post-translational modificationsand/or the interaction of LAP2� and other factors.

3. Role of A-type lamins in disease

In 1999, Bonne et al. described the first mutation in the LMNAgene linked to autosomal dominant Emery Dreifuss muscular dys-trophy (EDMD) [42]. Since then about 400 disease-linked mutationswere identified in A-type lamins and in several lamin-binding pro-teins of the nuclear envelope.

These mutations cause a variety of diseases, collectively termedprimary laminopathies for lamin A/C-linked diseases and nuclearenvelopathies for diseases linked to nuclear envelope proteins Theyaffect different tissues (striated muscle, heart, fat, bone, skin, orneuronal tissues) in isolation or in various combinations, or causepremature aging diseases, e.g., Hutchinson–Gilford Progeria Syn-drome (HGPS) [43–47].

Also a mutation in LAP2 ̨ has been linked to dilated cardiomy-opathy (DCM) [39], the pathological features of which resemblethose of lamin A-linked DCM. Interestingly, this DCM-causingLAP2� mutation, which leads to a single amino acid exchange inthe C-terminal lamin A/C-binding domain of LAP2� was shown toimpair LAP2�’s interaction with lamin A/C in vitro [39].

Most disease-causing mutations in the LMNA gene are heterozy-gous single point mutations in LMNA found throughout the gene,leading to the expression of mutant lamin A/C variants with a sin-gle amino acid exchange. In contrast, the majority of mutationslinked to HGPS introduce a cryptic splice site in exon 11 of LMNA,causing incorrect splicing and generation of a slightly smaller pre-lamin A variant (called progerin) that cannot be cleaved in the finalstep of post-translational processing and therefore remains perma-nently farnesylated [48]. Given that A-type lamins are expressedin nearly every differentiated cell, the tissue-specific phenotypesof many laminopathies are surprising, and the molecular pathwaysleading to the different pathological phenotypes are still not under-stood. Several non-mutually exclusive disease mechanisms havebeen proposed to explain the tissue-specific aspects and variabilityof laminopathic phenotypes [49,50].

ptide (LAP)2� and nucleoplasmic lamins in adult stem cell regulationb.2013.12.009

3.1. The mechanical model

LMNA mutations may disrupt the stability or assembly of laminnetworks, rendering the nucleus more fragile and less resistant

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o mechanical stress, ultimately leading to structural damage andell death in mechanically stressed tissues [51]. This model isupported by reports that lamin A/C-deficient fibroblasts, as wells cells derived from several laminopathy patients have abnor-ally shaped nuclei [52–54], and skeletal muscle from EDMD

atients and mouse disease models exhibit fragmented nuclei55,56]. Biomechanical studies showed that, unlike B-type lamins,amins A/C are the primary contributors to nuclear mechan-cs [54,57]. Accordingly, lamin A/C-deficient fibroblasts showecreased nuclear and cytoskeletal mechanical stiffness, increaseduclear fragility and impaired activation of mechanosensitiveenes [58–61]. Mutations in A-type lamins can also disrupt nucleo-ytoskeletal coupling, leading to a disturbance of nuclear anchoragend impaired ability to transmit intracellular forces between theytoskeleton and nuclear interior [51,62]. Therefore, the mechan-cal model may best describe muscular-dystrophy laminopathies,s muscles are exposed to high physical forces. For instance, cellsxpressing Familial Partial Lipodystrophy (FPLD)-linked lamin A/Cutants have normal nuclear stiffness, while mutations linked to

DMD and DCM result in a loss of nuclear stability [51].

.2. The gene regulation model

This model proposes that mutations in A-type lamins or theirssociated proteins cause dysregulation of tissue-specific genes46]. The altered regulation of genes may be caused by thempairment of heterochromatin formation and epigenetic path-

ays found in many laminopathic cells and in Lmna−/− mouseells [63–65]. Lamins can also affect signaling and gene expres-ion by direct interactions with transcription factors and signalingolecules. In particular, signaling pathways involved in the reg-

lation of proliferation and differentiation have been found to beffected in laminopathies, including pRb, mitogen activated pro-

Please cite this article in press as: Gesson K, et al. Lamina-associated polypeand disease. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcd

ein kinase (MAPK), Notch, transforming growth factor � (TGF-�),terol response element binding protein-1 (SREBP-1), NF-�B and

nt/�-catenin pathways [4,10]. In support of this notion, cellsnd tissues derived from EDMD and DCM mouse models and

ype lamins and nucleoplasmic A-type lamins, alone or in complex with LAP2�, may

patients show upregulated MAPK signaling [66], and HGPS patientcells present defective Wnt-, Notch- and pRb signaling [67–69]. Inaddition, in mouse models for progeria, NF-�B signaling was con-stitutively hyperactivated, leading to upregulation of inflammatorycytokines [70]. Lamin A/C-deficient cells show impaired activationof mechanosensitive genes (Egr1, lex1 and Mlk1) and decreased NF-�B signaling [59,60,71], thus potentially linking the mechanical andgene regulation disease models.

3.3. The stem cell model

At the cellular level, this model proposes that mutations inLMNA result in proliferation and differentiation defects, which maywell be directly linked to the mechanic and/or gene regulationdefects mentioned above. This model is based on findings thatA-type lamins interact functionally with two important regula-tors of G1 to S phase cell cycle progression, pRb and cyclin D3[37,72,73] (see Section 4.1). Human HGPS fibroblasts show rapidgrowth at early passages, but undergo premature senescence athigher passage numbers [74], and murine progeria fibroblasts alsoundergo premature cellular senescence [75]. Both, mesenchymalstem cells expressing progerin [76] and epidermal stem cells in skinof progeria mice [67] display impaired proliferation and/or differ-entiation. Loss of wild-type lamin A/C or the expression of EDMDlamin A/C mutants compromise myoblast differentiation [77,78],and overexpression of wild-type lamin A or FPLD-linked lamin Amutants affect adipocyte differentiation [79]. Lamins A/C appearto be involved also in osteoblast differentiation, as knock-downof lamin A/C caused impaired osteoblastogenesis and acceleratedosteoclastogenesis in human bone marrow stromal cells [80,81].

4. Functions of nucleoplasmic lamin A/C–LAP2� complexesand their link to disease

ptide (LAP)2� and nucleoplasmic lamins in adult stem cell regulationb.2013.12.009

To date, only a handful of studies have addressed the potentialfunctions of nucleoplasmic A-type lamins as opposed to those oflamins at the nuclear periphery. However, many of the described

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unctions of lamins, which intrinsically have been linked to theeripheral lamina, may partly or predominantly require their pres-nce within the nucleus. It is plausible to assume that, similar to theamina, nucleoplasmic lamin A/C complexes can serve as a scaffoldor signaling molecules [4,82] and may contribute to chromatinrganization and epigenetic regulation of genes in the nuclearnterior [83]. They may even contribute to nuclear mechanicsy stabilizing an intranuclear meshwork that absorbs mechanicalorces evenly like a sponge [60].

As in classical lamin A/C knock-out experiments or by expres-ion of mutant versions of lamin A/C both lamin pools are likely toe affected, it is difficult to distinguish between peripheral versusucleoplasmic lamin functions. Hence, the LAP2� knock-out mice,isplaying significantly reduced levels of nucleoplasmic lamins A/C,rovide an experimental system to selectively study the functionsf A-type lamins in the nuclear interior [24].

.1. Nucleoplasmic LAP2˛–lamin A/C complexes in proliferationnd differentiation

Both LAP2� [36,37] and lamins A and C [84,85] bind pRb initro and in vivo. pRb is a major cell cycle regulator that represseshe activity of E2F transcription factors and thereby inhibits cellycle progression in a phosphorylation-dependent manner [86].n the absence of mitogenic signals or upon differentiation, pRbs hypo-phosphorylated, binds to E2F and inhibits E2F target generanscription, allowing cells to exit the cell cycle. In the presencef mitogenic signals, pRb is heavily phosphorylated by cyclin-ependent kinases, causing release from E2F transcription factors,ctivation of E2F-dependent transcription and cell cycle progres-ion. This basic pRb cell proliferation-regulating cycle is subject tourther control by many additional pathways and feedback loops,ome of which may also include nucleoplasmic A-type lamins.

Several mechanisms have been proposed to explain how nucleo-lasmic lamin A/C and LAP2� affect pRb function (Fig. 2): (i) A-type

amins may stabilize pRb protein, since pRb was degraded via theroteosomal pathway in lamin A/C-deficient cells [72]. (ii) A-type

amins may provide a scaffold for efficient dephosphorylation ofRb by PP2A protein phosphatase upon TGFß-induced cell cyclerrest [87]. (iii) Interaction of pRb with A-type lamins may keep pRbn its active (repressive) hypo-phosphorylated state. Upon growthtimulation, ERK kinase translocates to the nucleus and may com-ete with pRb for binding to lamins A/C, causing release of pRb and

ts efficient phosphorylation by cyclin-dependent kinases [88]. (iv) complex of LAP2�, lamin A/C and hypo-phosphorylated pRb [37]ay be involved in efficient E2F target gene repression [36].In accordance with these mechanisms, nucleoplasmic lamins

/C and LAP2� were found to negatively affect cell cycle progres-ion and thus enhance cell cycle arrest in tissue progenitor cells ofegenerating tissues. Overexpression of LAP2� in cultured murinere-adipocytes drives cells into cell cycle exit and initiates differen-iation in the absence of hormones [36]. In contrast, loss of LAP2�mpairs efficient cell cycle exit by contact inhibition in primary

urine fibroblasts [24]. LAP2�-deficient myoblasts express higherevels of stemness factors compared to wild-type cells and showelayed differentiation in vivo [89]. Correspondingly, in LAP2�-eficient mice, the number of proliferating tissue progenitor cellsas significantly increased in skin, colon, skeletal muscle, and in theematopoietic system [24,40,89,90]. Furthermore, loss of LAP2� in

amin A/C-deficient mice, which lack wild-type lamin A but expressow levels of a lamin A �8–11 variant in some cells and tissues91], prolonged life span of double mutant mice from 30 to 70 days

Please cite this article in press as: Gesson K, et al. Lamina-associated polypeand disease. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcd

nd partially rescued the muscle growth phenotype [92], proba-ly by promoting proliferation of muscle progenitor cells. Thesendings suggest that nucleoplasmic lamin A/C–LAP2� complexesermit and/or promote differentiation of tissue progenitor cells and

PRESSpmental Biology xxx (2014) xxx– xxx

may thus be involved in tissue homeostasis by controlling the bal-ance between proliferation and differentiation of adult stem cellsas described in the following section.

4.2. Lamins in stem cell regulation

A-type lamins are absent or expressed at very low levels inundifferentiated embryonic stem cells (ESCs), and are upregulatedonly during cell differentiation [93,94]. Furthermore, upon repro-gramming of somatic fibroblasts to induced pluripotent stem (iPS)cells, lamin A levels are vastly decreased. Knockdown of laminA during reprogramming facilitates iPS cell generation, whereasoverexpression inhibits the induction of pluripotency and drivesdifferentiation [95].

While A-type lamins may be less important for initiation of EScell differentiation, they may have important regulatory roles insomatic (adult) stem cells (ASCs). These are tissue-specific stemcells which serve as a clonogenic, self-renewing reservoir with thecapability to differentiate into multiple cell lineages and are respon-sible for maintaining tissue homeostasis in adult organism byreplenishing dying and non-functional cells [96]. Adult stem cellsinclude hematopoietic and mesenchymal stem cells (MSCs). MSCsdifferentiate to committed precursor cells important for the regen-eration of muscle, heart, bone, adipose, nerve and skin tissue, allof which are severely affected in different laminopathies. There isevidence that A-type lamins are important for regulating the main-tenance and differentiation of both MSCs and tissue progenitorcells by influencing key signaling pathways [49,97]. Downregu-lation of A-type lamins or expression of HGPS lamin A variantin MSCs affects osteogenic, chondrogenic and adipogenic differ-entiation [76,81,98]. Furthermore, in two different HGPS mousemodels, epidermal stem cells were depleted causing an inflam-matory response [67,99]. Muscle-derived stem/progenitor cells(MDPSCs) from progeria mice also displayed defective proliferationand differentiation [100]. Interestingly, intraperitoneal administra-tion of MDPSCs derived from young wild-type mice to progeroidmice leads to significant extension of lifespan, suggesting thatimpaired MDPSC function in progeria mice results in a reduced lifeexpectancy.

Altogether, the findings that lamins alter adult stem cell functionled to the hypothesis that at least part of the phenotypes observedin laminopathies are due to defects in stem cell-mediated tissueregeneration [49,101]. Increased turnover and abnormal differenti-ation of adult stem cells in laminopathies may also deplete the stemcell pool. The stem cell defect, coupled with a potentially increasedmechanical sensitivity, could result in an inefficient repair of dam-aged tissues in HGPS and other laminopathies [101–103].

4.3. Impaired proliferation/differentiation pathways inlaminopathies

Many mutations linked to laminopathies affect the localizationof A-type lamins, either increasing or decreasing the nucleoplasmicpool of A-type lamins or leading to aggregation of mutant laminsin the nucleoplasm [104–107]. Therefore, it is conceivable that atleast some of the molecular defects underlying laminopathies arelinked to a misregulation of the functions of nucleoplasmic laminsA/C. Based on the role of nucleoplasmic lamins A/C and LAP2� inpRb-mediated cell cycle control (Fig. 2), it is tempting to speculatethat mutations in these proteins affect pRb-mediated pathways andderail the balance between proliferation/self-renewal and differ-entiation of tissue progenitor cells. EDMD- or HGPS-linked lamin A

ptide (LAP)2� and nucleoplasmic lamins in adult stem cell regulationb.2013.12.009

mutants impair phosphorylation of pRb [41,108], which may leadto premature cell cycle exit and senescence and to the inhibitionof differentiation [109,110]. In addition, pRb is downregulated inthe Zinc metalloproteinase Ste24 homolog (Zmpste24)−/− progeria

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ig. 2. A-type lamins and LAP2� affect the cell cycle-regulating functions of pRbifferentiation of adult stem cells. Disease linked perturbations of lamins A/C and/o

ouse model [111], and genome-wide expression analysis identi-ed the lamin A-pRb signaling network as a major pathway affected

n HGPS [69]. Also the abnormal pRb localization in laminopathies112] could further contribute to pRb dysregulation.

Besides its role in cell cycle control, pRb has well-establishedunctions in the differentiation of muscle, adipose tissue, bone,nd epidermis, all of which are affected in laminopathies. TheRb/MyoD pathway is the master regulator of myogenesis in skele-al muscle. pRb interacts with the myogenic transcription factor

yoD, subsequently activating MyoD-target genes and therebynitiating myoblast differentiation [113]. Thus, defects of the pRbathway in laminopathies may not only affect cell cycle exit, butay also impair pRb’s role in differentiation [103]. In line with

his model, Lmna-deficient skeletal myocytes express lower levelsf MyoD protein and consequently exhibit impaired MyoD/Rb-ediated in vitro myogenesis [77,78].Besides pRb pathways, other differentiation-mediating signal-

ng pathways were shown to be affected in mutant cells andissues. The aberrant differentiation of MSCs ectopically expressing

Please cite this article in press as: Gesson K, et al. Lamina-associated polypeand disease. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcd

rogerin was linked to increased Notch signaling [76]. Wild-typeamin A associates with the Notch co-activator SKIP, therebycavenging SKIP and reducing Notch-dependent transcriptionalctivity. Progerin has reduced affinity for SKIP leading to an

veral mechanisms (for details see text) balancing proliferation/self-renewal and� may result in an imbalance between these two cell fates.

increase in SKIP availability and activation of Notch downstreameffectors. Moreover, the Wnt/�-catenin pathway, which is knownto promote stem cell proliferation in stem-cell niches of theintestine, bone marrow, brain, and epidermis, was found to beattenuated in HGPS mouse models, altering extracellular matrixproduction [68].

5. Lamins in chromatin organization and implication forlaminopathies

Chromatin is non-randomly organized in the nucleus throughformation of chromosome territories [114] and associations withthe NE/nuclear lamina and possibly other structural components inthe nucleus [7,115,8]. A-type lamins have long been proposed to beinvolved in the spatial organization of chromatin due to their abilityto interact with DNA and core histones [11]. Similarly, several laminbinding proteins, including Lamin B Receptor (LBR) and the LEMproteins [15,30] have been shown to interact with chromatin. How-

ptide (LAP)2˛ and nucleoplasmic lamins in adult stem cell regulationb.2013.12.009

ever, only recently a few studies revealed two redundant pathwaystethering chromatin to the periphery, an LBR-mediated anchor-age (probably involving B-type lamins) and an A-type lamin-LEMprotein-dependent mechanism [116,117].

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.1. The role of the nuclear lamina in chromatin organization andene expression

The implementation of the DamID method using a DNA adenineethyltransferase (Dam)-lamin B1 fusion protein led to the first

enome-wide map of in vivo nuclear lamina–chromatin interac-ions [118,119]. The identified lamina-associated domains (LADs)ere shown to be large-scale, yet sharply confined genomic regions

f 0.1–10 Mb in size, which have transcriptional repressive fea-ures and represent gene-poor and heterochromatic regions withignificant enrichments of repressive histone marks (H3K27me3,3K9me3) [120]. This led to the concept that the nuclear periphery

s an overall transcriptionally repressive environment as opposedo the transcriptionally permissive conditions in the nucleoplasm83]. This model was supported by experiments showing thatrtificial tethering of genomic loci to the NE leads, at least inome cases, to their silencing [121–123]. Furthermore, genome-ntegrated arrays containing tissue-specific promoters were foundo localize at the periphery in embryos and translocated to theuclear center upon differentiation-dependent promoter activa-ion [124]. Additionally, a lamin B1-DamID approach trackingamina–chromatin interactions during differentiation of murineSCs to neuronal precursor cells and to terminally differentiatedstrocytes showed that previously stably NE-associated genes orene clusters detach from the NE and subsequently become acti-ated during differentiation [125]. These experiments indicatedhat the NE not only anchors heterochromatin, but may also activelyontribute to the generation of a heterochromatic, transcriptionallyilent environment. However, detachment from the NE per se doesot necessarily trigger immediate activation, but may poise genes

or later activation during terminal differentiation.Opposing the view that NE–chromatin interactions are stable in

he sense that they are inherited from mother to daughter cells, aecent study showed that in a given cell only 30% of all LADs aressociated with the NE and are stochastically reshuffled after mito-is [126]. It remains to be investigated whether LADs containingissue-specific genes are more specifically tethered to the NE duringifferentiation. Also, the “signature” (i.e., the epigenetic and geneticrofile) of chromatin mediating its association at the NE is poorlynderstood. A few recent studies have identified the heterochro-atic histone mark, H3K9me2 [126,127], A/T rich sequences [128],

r GAGA motifs [129] as important determinants for chromatin–NEethering.

.2. A-type lamins and chromatin regulation

Considering the dual location of A-type lamins at the nuclearamina and in the nucleoplasm, as opposed to the exclusive periph-ral localization of B-type lamins, it is conceivable that A-typeamins may also interact with chromatin in the nuclear interiorFig. 1). At the NE, certain chromatin attachment regions maye common for both A- and B-type lamins, while other genomicegions may be exclusive to one or the other. In support of this,himi et al. found that A- and B-type lamins form distinct, but inter-onnected, networks at the nuclear lamina [130]. While the termLAD” was originally coined for lamin B1–chromatin interactions,t appears to be extendable toward the association of lamin A withhromosomes at the NE. Genomic DamID maps for lamin A–Damusion proteins in human and murine cells are very similar to theenomic lamin B1 DamID maps, and constitutive NE–chromatinssociations (cLADs) are highly conserved across species and cellypes [128]. In addition to regions generally not associated with

Please cite this article in press as: Gesson K, et al. Lamina-associated polypeand disease. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcd

he lamina (constitutive inter-LADs), certain regions were found toacultatively interact with A- and B-type lamins in the course ofineage commitment, and do so with a potential preference for oner the other lamin type [128].

PRESSpmental Biology xxx (2014) xxx– xxx

A recent study by Kubben et al. [131] shed light on the in vivochromatin interactions of wildtype versus mutant lamin A linkedto HGPS (progerin). In a genome-wide analysis of promoter inter-actions, they showed a preference of A-type lamins for binding topromoters of silent or lowly expressed genes preferentially locatedat the nuclear periphery. Progerin–promoter interactions over-lapped to a large extent with that of wild-type lamin A, but a fewprogerin-specific (inherently silent) gene promoters were iden-tified. This extensive overlap of wildtype lamin A and progerinpromoter interactions is surprising, given that progerin appears tohave reduced binding affinity to DNA and H3K27 trimethylated his-tones [132]. While the former study used overexpressed lamin Aand progerin, genome interaction mapping of endogenous laminA and progerin revealed global changes in the heterochromaticmark H3K27me3, which appeared to be lost in gene-poor regionsin the mutant cells and appeared stronger in gene-rich regions,resulting in the detachment from the nuclear lamina of gene-poorheterochromatic regions [133].

Another recent study on genome-wide lamin A/C-promoterassociation during adipogenic differentiation identified lamin-richdomains (LRDs) throughout the genome in a manner consistentwith lamin A/C–promoter interactions not being restricted to thenuclear periphery [134]. Complementary to previous findings, thisstudy showed that binding of lamin A/C fine-tunes target generegulation depending on the local chromatin environment in spe-cific promoter subregions. The results indicate that lamin A/Cassociation with promoters per se does not inhibit transcription,but additionally requires certain repressive histone marks in sub-promoter regions; conversely, loss of lamin A/C from promoters isa prerequisite, but not sufficient for transcriptional activation.

LAP2� is a potential candidate for mediating the interaction ofnucleoplasmic lamins A/C with chromatin. LAP2� possesses a LEMand LEM-like domain [30], and thereby binds to chromatin in asequence – independent manner. In human cells, LAP2� was foundto interact with genomic DNA in a highly dynamic manner and toaffect the chromatin-binding behavior of the high-mobility groupN protein 5 (HMGN5) [135]. Downregulation of LAP2� led to theredistribution of HMGN5-targeted chromatin sites. Based on thesefindings it is tempting to speculate that LAP2� could also affect thechromatin interaction of other proteins in the nuclear interior, suchas nucleoplasmic lamin A/C.

In conclusion, A-type lamins not only ensure structural integrityof (metazoan) nuclei, but also maintain the balance between dif-ferentiation and proliferation. In part, these activities may rely onlamin A/C-binding proteins, such as LAP2�. The potential effects oflaminopathy-linked lamin mutants on chromatin organization mayalter gene expression by destabilization of higher-order chromatinstructure and/or interference with the binding of A-type lamins toother proteins. These perturbations may particularly affect stemcell homeostasis.

Acknowledgements

We thank Thomas Dechat, MFPL, for valuable discussions andWolfgang J. Schneider for carefully reading the manuscript. Work inthe authors’ laboratory was supported by grants from the AustrianScience Fund (FWF P22043-B12 and P23805-B2) to RF. KG and SVare members of doctoral program funded by Austrian Science Fund(FWF, DK W1220).

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