Changes in nuclear pore numbers control nuclear import and stress response of mouse hearts

Han, Lu; Mich-Basso, Jocelyn Danielle; Li, Yao; Ammanamanchi, Niyatie; Xu, Jianquan; Bargaje, Anita; Liu, Honghai; Wu, Liwen; Jeong, Jong‐Hyeon; Franks, Jonathan; Stolz, Donna B.; Wu, Yijen; Rajasundaram, Dhivyaa; Liu, Yang; Kühn, Bernhard

doi:10.1016/j.devcel.2022.09.017

Cited by 11 publications

(29 citation statements)

References 40 publications

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“…Consistent with this finding, cytoplasmic NUPs have been observed in muscle tissue from individuals with LMNA-associated muscular dystrophy [ 91 ]. Thus, the mechanisms by which LamC R564P causes muscular dystrophy might be due to alterations in nuclear import/export as seen in mouse hearts under stress [ 92 ].…”

Section: Resultsmentioning

confidence: 99%

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

Walker

Langland

Viles³

et al. 2023

Cells

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Mutations in the LMNA gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The LMNA gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork underlying the inner nuclear membrane. Lamins have a conserved domain structure consisting of a head, coiled-coil rod, and C-terminal tail domain possessing an Ig-like fold. This study identified differences between two mutant lamins that cause distinct clinical diseases. One of the LMNA mutations encodes lamin A/C p.R527P and the other codes lamin A/C p.R482W, which are typically associated with muscular dystrophy and lipodystrophy, respectively. To determine how these mutations differentially affect muscle, we generated the equivalent mutations in the Drosophila Lamin C (LamC) gene, an orthologue of human LMNA. The muscle-specific expression of the R527P equivalent showed cytoplasmic aggregation of LamC, a reduced larval muscle size, decreased larval motility, and cardiac defects resulting in a reduced adult lifespan. By contrast, the muscle-specific expression of the R482W equivalent caused an abnormal nuclear shape without a change in larval muscle size, larval motility, and adult lifespan compared to controls. Collectively, these studies identified fundamental differences in the properties of mutant lamins that cause clinically distinct phenotypes, providing insights into disease mechanisms.

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Section: Resultsmentioning

confidence: 99%

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

Walker

Langland

Viles³

et al. 2023

Cells

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“…Moreover, whether polyploidy contributes to the functional maturation needs further characterization. Interestingly, a recent work discovered that lamin B2 levels control nuclear pore numbers during cardiomyocyte maturation and subsequently alter nuclear import of signal proteins ( Han et al, 2022 ). It provides a new perspective to further investigate whether the nuclear pore dynamics influence the gene transcription related to proliferation and cellular maturation of cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from LMNB2-inactivated induced pluripotent stem cells

Wang

Morgan

Saini

et al. 2022

Front. Cell Dev. Biol.

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Mammalian cardiomyocyte maturation entails phenotypic and functional optimization during the late fetal and postnatal phases of heart development, both processes driven and coordinated by complex gene regulatory networks. Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) are heterogenous and immature, barely resembling their adult in vivo counterparts. To characterize relevant developmental programs and maturation states during human iPSC-cardiomyocyte differentiation, we performed single-cell transcriptomic sequencing, which revealed six cardiomyocyte subpopulations, whose heterogeneity was defined by cell cycle and maturation states. Two of those subpopulations were characterized by a mature, non-proliferative transcriptional profile. To further investigate the proliferation-maturation transition in cardiomyocytes, we induced loss-of-function of LMNB2, which represses cell cycle progression in primary cardiomyocytes in vivo. This resulted in increased maturation in LMNB2-inactivated cardiomyocytes, characterized by transcriptional profiles related to myofibril structure and energy metabolism. Furthermore, we identified maturation signatures and maturational trajectories unique for control and LMNB2-inactivated cardiomyocytes. By comparing these datasets with single-cell transcriptomes of human fetal hearts, we were able to define spatiotemporal maturation states in human iPSC-cardiomyocytes. Our results provide an integrated approach for comparing in vitro-differentiated cardiomyocytes with their in vivo counterparts and suggest a strategy to promote cardiomyocyte maturation.

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“…Furthermore, a DUSP6 inhibitor has been tested in myocardial infarction rats, showing that it improves heart function and suppresses inflammatory cardiac remodeling [ 65 ]. In addition, the cardiac-derived ECM may provide an ideal scaffold for heart tissue engineering [ 66 ], and nuclear pore numbers are decreased during cardiomyocyte maturation, and this reduces nuclear responses to activation of MAPK induced by extracellular signals [ 67 ]. Activation of Nrf1, a stress-responsive transcription factor is seen in regenerating cardiomyocytes.…”

Section: Role Of Molecular Signalings In Heart Regenerationmentioning

confidence: 99%

Regeneration of the heart: from molecular mechanisms to clinical therapeutics

et al. 2023

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Heart injury such as myocardial infarction leads to cardiomyocyte loss, fibrotic tissue deposition, and scar formation. These changes reduce cardiac contractility, resulting in heart failure, which causes a huge public health burden. Military personnel, compared with civilians, is exposed to more stress, a risk factor for heart diseases, making cardiovascular health management and treatment innovation an important topic for military medicine. So far, medical intervention can slow down cardiovascular disease progression, but not yet induce heart regeneration. In the past decades, studies have focused on mechanisms underlying the regenerative capability of the heart and applicable approaches to reverse heart injury. Insights have emerged from studies in animal models and early clinical trials. Clinical interventions show the potential to reduce scar formation and enhance cardiomyocyte proliferation that counteracts the pathogenesis of heart disease. In this review, we discuss the signaling events controlling the regeneration of heart tissue and summarize current therapeutic approaches to promote heart regeneration after injury.

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Changes in nuclear pore numbers control nuclear import and stress response of mouse hearts

Cited by 11 publications

References 40 publications

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from LMNB2-inactivated induced pluripotent stem cells

Regeneration of the heart: from molecular mechanisms to clinical therapeutics

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