Nuclear Lamins in Cardiac Development and Disease
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis a nice, well-written and comprehensive review on the role of lamins in cardiac development and physiology. I have only a few questions/comments that, if addressed, will further strengthen the manuscript.
How do B-type lamins support early nuclear deformation and plasticity? Briefly addressing the underlying molecular mechanisms would be helpful.
If B-type lamins play prominent roles during embryonic development such as mediating nuclear deformation and proliferative competence of cardiomyocytes why human cardiac malfunctions caused by B-type lamin mutations are relatively rare?
The review centers on the peripheral positioning of heterochromatin via the association of Lamina-Associated Domains (LADs) with lamins. Solovei et al. (ref 115) identified LBR- and lamin-A/C-dependent mechanisms tethering heterochromatin to the NE. The two tethers are sequentially used during cellular differentiation and development, first the LBR- and then the lamin-A/C-dependent tether. At first, LBR is undervalued, receiving only a brief mention. Furthermore, and more importantly, lamin A/C predominantly binds chromatin indirectly, via a complex with LEM domain proteins. LEM domain proteins such as emerin, MAN1 and LAPs are essential for anchoring chromatin to the nuclear periphery, maintaining nuclear structure, and regulating gene expression, while mutations of these proteins are linked to laminopathic diseases such as muscular dystrophy and dilated cardiomyopathy. The manuscript would benefit from a discussion of these proteins.
Author Response
We sincerely thank you for the careful evaluation of our manuscript and for the constructive comments, which have greatly improved the quality and clarity of our review. Please find the detailed responses below and the corresponding revisions shown in blue font in the resubmitted manuscript.
Comments 1: How do B-type lamins support early nuclear deformation and plasticity? Briefly addressing the underlying molecular mechanisms would be helpful.
Response 1: Thank you for this valuable comment. We agree that a brief mechanistic clarification would strengthen the manuscript. In the revised manuscript, we have revised Section 3.4 to briefly incorporate the underlying molecular mechanisms by which B-type lamins support nuclear deformation and plasticity during organogenesis. During this stage, B-type lamins facilitate nuclear deformation required for cell migration within confined tissue environments.
Specifically, we have added a sentence describing how B-type lamins form a loosely spaced, deformable Lamin B1 filament network positioned near the inner nuclear membrane [1], [2], which is mechanically coupled to the cytoskeleton via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex [3], [4], [5], [6]. This organization facilitates force transmission and dissipation, thereby enabling nuclear plasticity during cell migration and tissue morphogenesis.
These revisions have been incorporated into Section 3.4 (lines 455-461).
Comments 2: If B-type lamins play prominent roles during embryonic development such as mediating nuclear deformation and proliferative competence of cardiomyocytes why human cardiac malfunctions caused by B-type lamin mutations are relatively rare?
Response 2: We appreciate your insightful question. We agree that this is an important point and that it is appropriate to address it in the manuscript. Several non-mutually exclusive factors may account for the relatively low incidence of cardiac phenotypes associated with B-type lamin mutations in humans.
First, B-type lamins primarily regulate fundamental cellular processes such as nuclear integrity, migration, and proliferation, whereas A-type lamins play a more prominent role in postnatal mechanical adaptation of cardiomyocytes. This functional divergence likely contributes to tissue-specific vulnerability, with LMNA mutations more frequently causing cardiomyopathy, while disease phenotypes associated with B-type lamins predominantly manifest in the nervous system rather than in cardiac tissue.
Second, B-type lamins are essential for early embryonic development, and severe loss-of-function mutations are often embryonically or perinatally lethal, thereby precluding the manifestation of postnatal cardiac phenotypes. Third, functional redundancy and compensatory mechanisms, including partial compensation between Lamin B1 and Lamin B2, as well as contributions from A-type lamins or other nuclear envelope components. Finally, it is also possible that subtle or developmental-stage-specific cardiac abnormalities related to B-type lamin dysfunction remain underrecognized in human studies.
We have now incorporated a brief discussion of these points in the revised manuscript to improve clarity (lines 768-780).
Comments 3: The review centers on the peripheral positioning of heterochromatin via the association of Lamina-Associated Domains (LADs) with lamins. Solovei et al. (ref 115) identified LBR- and lamin-A/C-dependent mechanisms tethering heterochromatin to the NE. The two tethers are sequentially used during cellular differentiation and development, first the LBR- and then the lamin-A/C-dependent tether. At first, LBR is undervalued, receiving only a brief mention. Furthermore, and more importantly, lamin A/C predominantly binds chromatin indirectly, via a complex with LEM domain proteins. LEM domain proteins such as emerin, MAN1 and LAPs are essential for anchoring chromatin to the nuclear periphery, maintaining nuclear structure, and regulating gene expression, while mutations of these proteins are linked to laminopathic diseases such as muscular dystrophy and dilated cardiomyopathy. The manuscript would benefit from a discussion of these proteins.
Response 3: We thank the reviewer for this insightful comment. We agree that the original manuscript placed relatively greater emphasis on lamins in mediating peripheral heterochromatin positioning. We have now revised the text to incorporate the concept that chromatin tethering to the nuclear envelope is mediated by multiple, developmentally regulated systems. Specifically, we expanded the discussion of the dual tethering model described by Solovei et al., highlighting the sequential use of an early LBR-dependent tether and a later Lamin A/C-dependent tether during differentiation. In addition, we clarified that Lamin A/C predominantly interacts with chromatin indirectly through LEM domain-containing proteins and have included a discussion of key LEM proteins such as emerin, MAN1, and LAP2, emphasizing their roles in chromatin anchoring, nuclear organization, and gene regulation, as well as their relevance to laminopathic diseases including dilated cardiomyopathy. These revisions have been incorporated into Section 3.1 (lines 308-326).
[1] S. Dutta, M. Bhattacharyya, and K. Sengupta, “Implications and Assessment of the Elastic Behavior of Lamins in Laminopathies,” Cells, vol. 5, no. 4, p. 37, Oct. 2016, doi: 10.3390/cells5040037.
[2] B. Nmezi et al., “Concentric organization of A- and B-type lamins predicts their distinct roles in the spatial organization and stability of the nuclear lamina,” Proceedings of the National Academy of Sciences, vol. 116, no. 10, pp. 4307–4315, Mar. 2019, doi: 10.1073/pnas.1810070116.
[3] M. Crisp et al., “Coupling of the nucleus and cytoplasm: role of the LINC complex,” J Cell Biol, vol. 172, no. 1, pp. 41–53, Jan. 2006, doi: 10.1083/jcb.200509124.
[4] D. A. Starr and H. N. Fridolfsson, “Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges,” Annu Rev Cell Dev Biol, vol. 26, pp. 421–444, 2010, doi: 10.1146/annurev-cellbio-100109-104037.
[5] A. Buxboim et al., “Scaffold, mechanics and functions of nuclear lamins,” FEBS Letters, vol. 597, no. 22, pp. 2791–2805, 2023, doi: 10.1002/1873-3468.14750.
[6] N. E. Cain, E. C. Tapley, K. L. McDonald, B. M. Cain, and D. A. Starr, “The SUN protein UNC-84 is required only in force-bearing cells to maintain nuclear envelope architecture,” J Cell Biol, vol. 206, no. 2, pp. 163–172, Jul. 2014, doi: 10.1083/jcb.201405081.
Reviewer 2 Report
Comments and Suggestions for AuthorsI have reviewed the manuscript titled “Nuclear Lamins in Cardiac Development and Disease”. This study addresses an important topic regarding nuclear lamins in cardiac tissue, and the findings offer meaningful insights into the field. However, in its current form, the manuscript requires significant revisions to improve its structural clarity and academic rigor. Specifically, there are issues with logical consistency and a lack of specific detail in the experimental descriptions. I believe the paper will be much improved if the authors carefully attend to the structural and technical details outlined below:
- There are numerous instances where citations are missing throughout the manuscript (e.g., lines 140, 220, 294, 303, 306, 309, 326, 423, 598, and so on). As these examples are not exhaustive, I strongly recommend a comprehensive review of the entire text to ensure that every claim is supported by the appropriate reference.
- There is significant redundancy across several paragraphs. While the function of proteins may share a similar objective, the underlying tissue environments and experimental contexts vary. Therefore, it is necessary to provide more detailed descriptions of the specific experimental conditions and situational variables to distinguish these findings clearly. I picked several sentences to show redundancy in below.
234 Under these conditions, the structural functions of Lamin A/C become increasingly important for maintaining nuclear integrity and
308 Lamin A/C becomes increasingly important for reinforcing nuclear structure and preserving nuclear integrity under load.
583 Lamins are also major determinants of nuclear mechanical properties. Experimental studies demonstrate that lamin composition strongly influences nuclear stiffness, with lamin deficiency producing mechanically fragile nuclei
617 Taken together, these observations indicate that lamins function as integrative regulators of nuclear physiology. By coordinating genome organization, mitotic progression, nucleocytoplasmic transport, and mechanotransduction, lamins align nuclear architecture with cellular state and environmental demands.
- The current manuscript feels a bit repetitive in certain areas, which makes the overall logic difficult to follow. I would suggest restructuring Section 2 and its subheadings for better clarity.
Specifically, it might be more effective to separate 'Lamin-A/C' from 'Lamin-B' entirely. Alternatively, you could first describe the general mechanism and then follow up with the specific characteristics found in cardiac tissue and its related cardiac disease. This structural change would make the progression much more intuitive for the reader.
- Additionally, I recommend avoiding the use of pronouns like 'This' or 'They' at the beginning of sentences. Instead, please use specific nouns to clearly identify the subject, which will enhance the academic precision of the text.
Author Response
We greatly appreciate your thorough evaluation of our manuscript and your constructive comments, which have significantly improved the quality and clarity of our review. Please find the detailed responses below and the corresponding revisions shown in blue font in the resubmitted manuscript.
Comments 1: There are numerous instances where citations are missing throughout the manuscript (e.g., lines 140, 220, 294, 303, 306, 309, 326, 423, 598, and so on). As these examples are not exhaustive, I strongly recommend a comprehensive review of the entire text to ensure that every claim is supported by the appropriate reference.
Response 1: We thank the reviewer for this important comment. We agree that appropriate citation is essential for ensuring the accuracy and rigor of a review article. To address this, we have conducted a comprehensive review of the entire manuscript and added references where needed to support all relevant statements, including but not limited to the examples highlighted by the reviewer. We have carefully ensured that general statements, mechanistic claims, and context-setting descriptions are now consistently supported by appropriate literature citations throughout the text.
Comments 2: There is significant redundancy across several paragraphs. While the function of proteins may share a similar objective, the underlying tissue environments and experimental contexts vary. Therefore, it is necessary to provide more detailed descriptions of the specific experimental conditions and situational variables to distinguish these findings clearly. I picked several sentences to show redundancy in below.
234 Under these conditions, the structural functions of Lamin A/C become increasingly important for maintaining nuclear integrity and
308 Lamin A/C becomes increasingly important for reinforcing nuclear structure and preserving nuclear integrity under load.
583 Lamins are also major determinants of nuclear mechanical properties. Experimental studies demonstrate that lamin composition strongly influences nuclear stiffness, with lamin deficiency producing mechanically fragile nuclei
617 Taken together, these observations indicate that lamins function as integrative regulators of nuclear physiology. By coordinating genome organization, mitotic progression, nucleocytoplasmic transport, and mechanotransduction, lamins align nuclear architecture with cellular state and environmental demands.
Response 2: Thank you for this helpful comment. We agree that some statements describing the structural and mechanical roles of lamins were presented in a way that could appear redundant across different sections. We have revised the manuscript to reduce repetition and to more clearly distinguish these statements based on their specific biological contexts, including developmental regulation, mechanical stress conditions, and biophysical characterization. We have also refined the wording throughout to ensure that similar concepts are presented with appropriate contextual specificity rather than repeated as general conclusions.
Comments 3: The current manuscript feels a bit repetitive in certain areas, which makes the overall logic difficult to follow. I would suggest restructuring Section 2 and its subheadings for better clarity.
Specifically, it might be more effective to separate 'Lamin-A/C' from 'Lamin-B' entirely. Alternatively, you could first describe the general mechanism and then follow up with the specific characteristics found in cardiac tissue and its related cardiac disease. This structural change would make the progression much more intuitive for the reader.
Response 3: Thank you for pointing out that Section 2 lacked clarity due to repetitive content and suboptimal organization. we have restructured Section 2 to improve its logical flow and readability. The revised section now follows the developmental timeline illustrated in Figure 1, first highlighting B-type lamins (Sections 2.2 and 2.3), followed by A-type lamins (Section 2.4).
In addition, Section 2.1 has been extensively condensed to provide a more concise overview. Sections 2.2 and 2.3 have also been revised, with text that potentially overlapped with adjacent sections removed or streamlined. The former Section 2.5 is replaced by a summary paragraph with condensed concept. Altogether, these revisions have streamlined the structure of Section 2 and made the progression of concepts more intuitive for the reader.
Comments 4: Additionally, I recommend avoiding the use of pronouns like 'This' or 'They' at the beginning of sentences. Instead, please use specific nouns to clearly identify the subject, which will enhance the academic precision of the text.
Response 4: We thank the reviewer for this helpful suggestion. We agree that avoiding ambiguous pronoun usage improves clarity and academic precision. Accordingly, we have systematically revised the manuscript to replace sentence-initial pronouns such as “This” and “They” with explicit nouns throughout the text. These changes have been implemented across the revised manuscript to improve readability and precision.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsCurrent advanced version of manuscript can be published.
