scholarly journals LINCking the Nuclear Envelope to Sperm Architecture

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 658
Author(s):  
Francesco Manfrevola ◽  
Florian Guillou ◽  
Silvia Fasano ◽  
Riccardo Pierantoni ◽  
Rosanna Chianese
Keyword(s):  
Nuclear Envelope ◽  
Male Fertility ◽  
Nuclear Architecture ◽  
Sperm Cells ◽  
Bridge Structure ◽  
Linc Complex ◽  
Head Formation ◽  
Morphological Maturation ◽  
Integral Proteins ◽  
Sun Domain

Nuclear architecture undergoes an extensive remodeling during spermatogenesis, especially at levels of spermatocytes (SPC) and spermatids (SPT). Interestingly, typical events of spermiogenesis, such as nuclear elongation, acrosome biogenesis, and flagellum formation, need a functional cooperation between proteins of the nuclear envelope and acroplaxome/manchette structures. In addition, nuclear envelope plays a key role in chromosome distribution. In this scenario, special attention has been focused on the LINC (linker of nucleoskeleton and cytoskeleton) complex, a nuclear envelope-bridge structure involved in the connection of the nucleoskeleton to the cytoskeleton, governing mechanotransduction. It includes two integral proteins: KASH- and SUN-domain proteins, on the outer (ONM) and inner (INM) nuclear membrane, respectively. The LINC complex is involved in several functions fundamental to the correct development of sperm cells such as head formation and head to tail connection, and, therefore, it seems to be important in determining male fertility. This review provides a global overview of the main LINC complex components, with a special attention to their subcellular localization in sperm cells, their roles in the regulation of sperm morphological maturation, and, lastly, LINC complex alterations associated to male infertility.

scholarly journals The testis-specific LINC component SUN3 is essential for sperm head shaping during mouse spermiogenesis

2020 ◽  
Vol 295 (19) ◽  
pp. 6289-6298 ◽  
Author(s):  
Qian Gao ◽  
Ranjha Khan ◽  
Changping Yu ◽  
Manfred Alsheimer ◽  
Xiaohua Jiang ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Male Fertility ◽  
Sperm Head ◽  
Mechanical Forces ◽  
Linc Complex ◽  
Sperm Counts ◽  
Sperm Nuclei ◽  
Sun Domain ◽  
Underlying Pathology

Sperm head shaping is a key event in spermiogenesis and is tightly controlled via the acrosome–manchette network. Linker of nucleoskeleton and cytoskeleton (LINC) complexes consist of Sad1 and UNC84 domain–containing (SUN) and Klarsicht/ANC-1/Syne-1 homology (KASH) domain proteins and form conserved nuclear envelope bridges implicated in transducing mechanical forces from the manchette to sculpt sperm nuclei into a hook-like shape. However, the role of LINC complexes in sperm head shaping is still poorly understood. Here we assessed the role of SUN3, a testis-specific LINC component harboring a conserved SUN domain, in spermiogenesis. We show that CRISPR/Cas9-generated Sun3 knockout male mice are infertile, displaying drastically reduced sperm counts and a globozoospermia-like phenotype, including a missing, mislocalized, or fragmented acrosome, as well as multiple defects in sperm flagella. Further examination revealed that the sperm head abnormalities are apparent at step 9 and that the sperm nuclei fail to elongate because of the absence of manchette microtubules and perinuclear rings. These observations indicate that Sun3 deletion likely impairs the ability of the LINC complex to transduce the cytoskeletal force to the nuclear envelope, required for sperm head elongation. We also found that SUN3 interacts with SUN4 in mouse testes and that the level of SUN4 proteins is drastically reduced in Sun3-null mice. Altogether, our results indicate that SUN3 is essential for sperm head shaping and male fertility, providing molecular clues regarding the underlying pathology of the globozoospermia-like phenotype.

scholarly journals A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte

2020 ◽  
Vol 126 (3) ◽  
Author(s):  
Julie Heffler ◽  
Parisha P. Shah ◽  
Patrick Robison ◽  
Sai Phyo ◽  
Kimberly Veliz ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Intermediate Filaments ◽  
Genome Organization ◽  
Contractile Function ◽  
Nuclear Architecture ◽  
Super Resolution ◽  
Nuclear Lamina ◽  
Linc Complex ◽  
Spectrin Repeat ◽  
Balance Of Forces

Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

scholarly journals Phosphorylation of luminal region of the SUN-domain protein Mps3 promotes nuclear envelope localization during meiosis

2020 ◽  
Author(s):  
H. B. D. Prasada Rao ◽  
Takeshi Sato ◽  
Kiran Challa ◽  
Miki Shinohara ◽  
Akira Shinohara
Keyword(s):  
Protein Kinase ◽  
Nuclear Envelope ◽  
Control Force ◽  
Linc Complex ◽  
Specific Localization ◽  
Domain Protein ◽  
Protein Ensembles ◽  
And Function ◽  
Sun Domain ◽  
Luminal Region

SummaryDuring meiosis, protein ensembles in the nuclear envelope (NE) containing SUN- and KASH-domain proteins, called linker nucleocytoskeleton and cytoskeleton (LINC) complex, promote chromosome motion. How LINC complexes acquire the meiotic property is largely unknown. Here we showed that cyclin-dependent protein kinase (CDK) and Dbf4-dependent Cdc7 protein kinase (DDK) promote proper meiosis-specific localization of yeast SUN-domain protein Mps3 on NE and control force-dependent movement of chromosomes during meiosis. We also found a NE luminal region of Mps3 juxtaposed to inner nuclear membrane (INM) is required for meiosis-specific localization of Mps3 on NE. Negative charges introduced by meiosis-specific non-canonical phosphorylation of the luminal region of Mps3 changes its interaction with INM, which may induce NE localization by promoting the formation of a canonical LINC complex with Mps3. Our study reveals unique phosphorylation-dependent regulation on the localization and function of Mps3 protein in meiotic NE remodeling.

scholarly journals Maize (Zea mays L.) Nucleoskeletal Proteins Regulate Nuclear Envelope Remodeling and Function in Stomatal Complex Development and Pollen Viability

2021 ◽  
Vol 12 ◽  
Author(s):  
Joseph F. McKenna ◽  
Hardeep K. Gumber ◽  
Zachary M. Turpin ◽  
Alexis M. Jalovec ◽  
Andre C. Kartick ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Zea Mays L ◽  
Fluorescent Protein ◽  
Pollen Viability ◽  
Nuclear Periphery ◽  
Nuclear Architecture ◽  
Linc Complex ◽  
Stomatal Complex ◽  
Complex Development ◽  
And Function

In eukaryotes, the nuclear envelope (NE) encloses chromatin and separates it from the rest of the cell. The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex physically bridges across the NE, linking nuclear and cytoplasmic components. In plants, these LINC complexes are beginning to be ascribed roles in cellular and nuclear functions, including chromatin organization, regulation of nuclei shape and movement, and cell division. Homologs of core LINC components, KASH and SUN proteins, have previously been identified in maize. Here, we characterized the presumed LINC-associated maize nucleoskeletal proteins NCH1 and NCH2, homologous to members of the plant NMCP/CRWN family, and MKAKU41, homologous to AtKAKU4. All three proteins localized to the nuclear periphery when transiently and heterologously expressed as fluorescent protein fusions in Nicotiana benthamiana. Overexpression of MKAKU41 caused dramatic changes in the organization of the nuclear periphery, including nuclear invaginations that stained positive for non-nucleoplasmic markers of the inner and outer NE membranes, and the ER. The severity of these invaginations was altered by changes in LINC connections and the actin cytoskeleton. In maize, MKAKU41 appeared to share genetic functions with other LINC components, including control of nuclei shape, stomatal complex development, and pollen viability. Overall, our data show that NCH1, NCH2, and MKAKU41 have characteristic properties of LINC-associated plant nucleoskeletal proteins, including interactions with NE components suggestive of functions at the nuclear periphery that impact the overall nuclear architecture.

scholarly journals Mouse models of nesprin-related diseases

2018 ◽  
Vol 46 (3) ◽  
pp. 669-681 ◽  
Author(s):  
Can Zhou ◽  
Li Rao ◽  
Derek T. Warren ◽  
Catherine M. Shanahan ◽  
Qiuping Zhang
Keyword(s):  
Nuclear Envelope ◽  
Mouse Models ◽  
Nuclear Architecture ◽  
Nuclear Lamina ◽  
Scaffolding Proteins ◽  
Linc Complex ◽  
Spectrin Repeat ◽  
Autosomal Recessive Cerebellar Ataxia ◽  
Range Of Functions ◽  
And Migration

Nesprins (nuclear envelope spectrin repeat proteins) are a family of multi-isomeric scaffolding proteins. Nesprins form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) complex with SUN (Sad1p/UNC84) domain-containing proteins at the nuclear envelope, in association with lamin A/C and emerin, linking the nucleoskeleton to the cytoskeleton. The LINC complex serves as both a physical linker between the nuclear lamina and the cytoskeleton and a mechanosensor. The LINC complex has a broad range of functions and is involved in maintaining nuclear architecture, nuclear positioning and migration, and also modulating gene expression. Over 80 disease-related variants have been identified in SYNE-1/2 (nesprin-1/2) genes, which result in muscular or central nervous system disorders including autosomal dominant Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy and autosomal recessive cerebellar ataxia type 1. To date, 17 different nesprin mouse lines have been established to mimic these nesprin-related human diseases, which have provided valuable insights into the roles of nesprin and its scaffold LINC complex in a tissue-specific manner. In this review, we summarise the existing nesprin mouse models, compare their phenotypes and discuss the potential mechanisms underlying nesprin-associated diseases.

scholarly journals Phosphorylation of luminal region of the SUN-domain protein Mps3 promotes nuclear envelope localization during meiosis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hanumanthu BD Prasada Rao ◽  
Takeshi Sato ◽  
Kiran Challa ◽  
Yurika Fujita ◽  
Miki Shinohara ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nuclear Envelope ◽  
Meiotic Chromosome ◽  
Linc Complex ◽  
Dependent Protein ◽  
Domain Protein ◽  
Protein Ensembles ◽  
Chromosome Motion ◽  
Sun Domain ◽  
Luminal Region

During meiosis, protein ensembles in the nuclear envelope (NE) containing SUN- and KASH-domain proteins, called linker nucleocytoskeleton and cytoskeleton (LINC) complex, promote the chromosome motion. Yeast SUN-domain protein, Mps3, forms multiple meiosis-specific ensembles on NE, which show dynamic localisation for chromosome motion; however, the mechanism by which these Mps3 ensembles are formed during meiosis remains largely unknown. Here, we showed that the cyclin-dependent protein kinase (CDK) and Dbf4-dependent Cdc7 protein kinase (DDK) regulate meiosis-specific dynamics of Mps3 on NE, particularly by mediating the resolution of Mps3 clusters and telomere clustering. We also found that the luminal region of Mps3 juxtaposed to the inner nuclear membrane is required for meiosis-specific localisation of Mps3 on NE. Negative charges introduced by meiosis-specific phosphorylation in the luminal region of Mps3 alter its interaction with negatively charged lipids by electric repulsion in reconstituted liposomes. Phospho-mimetic substitution in the luminal region suppresses the localisation of Mps3 via the inactivation of CDK or DDK. Our study revealed multi-layered phosphorylation-dependent regulation of the localisation of Mps3 on NE for meiotic chromosome motion and NE remodelling.

scholarly journals Maize (Zea mays L.) nucleoskeletal proteins regulate nuclear envelope remodeling and function in stomatal complex development and pollen viability.

2020 ◽  
Author(s):  
JF McKenna ◽  
HK Gumber ◽  
ZM Turpin ◽  
AM Jalovec ◽  
AC Kartick ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Zea Mays L ◽  
Fluorescent Protein ◽  
Pollen Viability ◽  
Nuclear Periphery ◽  
Nuclear Architecture ◽  
Linc Complex ◽  
Stomatal Complex ◽  
Complex Development ◽  
And Function

ABSTRACTIn eukaryotes, the nuclear envelope (NE) encloses chromatin and separates it from the rest of the cell. The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex physically bridges across the NE, linking nuclear and cytoplasmic components. In plants, these LINC complexes are beginning to be ascribed roles in cellular and nuclear functions, including chromatin organization, regulation of nuclei shape and movement, and cell division. Homologs of core LINC components, KASH and SUN proteins, have previously been identified in maize. Here, we characterized the presumed LINC-associated maize nucleoskeletal proteins NCH1 and NCH2, homologs of members of the plant NMCP/CRWN family, and MKAKU41, homologous to AtKAKU4. All three proteins localized to the nuclear periphery when transiently and heterologously expressed as fluorescent protein fusions in Nicotiana benthamiana. Overexpression of MKAKU41 caused dramatic changes in the organization of the nuclear periphery, including nuclear invaginations that stained positive for non-nucleoplasmic markers of the inner and outer NE, and the ER. The severity of these invaginations was altered by changes in LINC connections and the actin cytoskeleton. In maize, MKAKU41 appeared to share genetic functions with other LINC components, including control of nuclei shape, stomatal complex development, and pollen viability. Overall, our data show that NCH1, NCH2, and MKAKU41 have characteristic properties of LINC-associated plant nucleoskeletal proteins, including interactions with NE components suggestive of functions at the nuclear periphery that impact the overall nuclear architecture.

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

2005 ◽  
Vol 23 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Ilaria Filesi ◽  
Francesca Gullotta ◽  
Giovanna Lattanzi ◽  
Maria Rosaria D'Apice ◽  
Cristina Capanni ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Protein A ◽  
Nuclear Architecture ◽  
Mendelian Inheritance ◽  
Premature Aging ◽  
Lamin A ◽  
Lamin B ◽  
Lamin B Receptor ◽  
Epigenetic Events ◽  
Mandibuloacral Dysplasia

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

scholarly journals Coupling of the nucleus and cytoplasm: Role of the LINC complex

2005 ◽  
Vol 172 (1) ◽  
pp. 41-53 ◽  
Author(s):  
Melissa Crisp ◽  
Qian Liu ◽  
Kyle Roux ◽  
J.B. Rattner ◽  
Catherine Shanahan ◽  
...  
Keyword(s):  
Nuclear Membrane ◽  
Integral Membrane Proteins ◽  
Actin Binding ◽  
Linc Complex ◽  
Outer Membranes ◽  
Perinuclear Space ◽  
Actin Binding Domain ◽  
Lumenal Domain ◽  
Integral Proteins

The nuclear envelope defines the barrier between the nucleus and cytoplasm and features inner and outer membranes separated by a perinuclear space (PNS). The inner nuclear membrane contains specific integral proteins that include Sun1 and Sun2. Although the outer nuclear membrane (ONM) is continuous with the endoplasmic reticulum, it is nevertheless enriched in several integral membrane proteins, including nesprin 2 Giant (nesp2G), an 800-kD protein featuring an NH2-terminal actin-binding domain. A recent study (Padmakumar, V.C., T. Libotte, W. Lu, H. Zaim, S. Abraham, A.A. Noegel, J. Gotzmann, R. Foisner, and I. Karakesisoglou. 2005. J. Cell Sci. 118:3419–3430) has shown that localization of nesp2G to the ONM is dependent upon an interaction with Sun1. In this study, we confirm and extend these results by demonstrating that both Sun1 and Sun2 contribute to nesp2G localization. Codepletion of both of these proteins in HeLa cells leads to the loss of ONM-associated nesp2G, as does overexpression of the Sun1 lumenal domain. Both treatments result in the expansion of the PNS. These data, together with those of Padmakumar et al. (2005), support a model in which Sun proteins tether nesprins in the ONM via interactions spanning the PNS. In this way, Sun proteins and nesprins form a complex that links the nucleoskeleton and cytoskeleton (the LINC complex).

scholarly journals Nuclear envelope rupture is induced by actin-based nucleus confinement

2016 ◽  
Vol 215 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Emily M. Hatch ◽  
Martin W. Hetzer
Keyword(s):  
Nuclear Envelope ◽  
Cancer Cells ◽  
Nuclear Membrane ◽  
Nuclear Lamina ◽  
Membrane Stability ◽  
Linc Complex ◽  
Actin Bundles ◽  
In Cells

Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.

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