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6 results on '"Vahabikashi A"'

1. Nuclear lamin isoforms differentially contribute to LINC complex-dependent nucleocytoskeletal coupling and whole-cell mechanics.

Author

Vahabikashi, Amir, Vahabikashi, Amir, Sivagurunathan, Suganya, Nicdao, Fiona, Han, Yu, Park, Chan, Kittisopikul, Mark, Wong, Xianrong, Tran, Joseph, Gundersen, Gregg, Reddy, Karen, Luxton, G, Guo, Ming, Fredberg, Jeffrey, Zheng, Yixian, Adam, Stephen, Goldman, Robert, Vahabikashi, Amir, Vahabikashi, Amir, Sivagurunathan, Suganya, Nicdao, Fiona, Han, Yu, Park, Chan, Kittisopikul, Mark, Wong, Xianrong, Tran, Joseph, Gundersen, Gregg, Reddy, Karen, Luxton, G, Guo, Ming, Fredberg, Jeffrey, Zheng, Yixian, Adam, Stephen, and Goldman, Robert

Abstract

The ability of a cell to regulate its mechanical properties is central to its function. Emerging evidence suggests that interactions between the cell nucleus and cytoskeleton influence cell mechanics through poorly understood mechanisms. Here we conduct quantitative confocal imaging to show that the loss of A-type lamins tends to increase nuclear and cellular volume while the loss of B-type lamins behaves in the opposite manner. We use fluorescence recovery after photobleaching, atomic force microscopy, optical tweezer microrheology, and traction force microscopy to demonstrate that A-type lamins engage with both F-actin and vimentin intermediate filaments (VIFs) through the linker of nucleoskeleton and cytoskeleton (LINC) complexes to modulate cortical and cytoplasmic stiffness as well as cellular contractility in mouse embryonic fibroblasts (MEFs). In contrast, we show that B-type lamins predominantly interact with VIFs through LINC complexes to regulate cytoplasmic stiffness and contractility. We then propose a physical model mediated by the lamin–LINC complex that explains these distinct mechanical phenotypes (mechanophenotypes). To verify this model, we use dominant negative constructs and RNA interference to disrupt the LINC complexes that facilitate the interaction of the nucleus with the F-actin and VIF cytoskeletons and show that the loss of these elements results in mechanophenotypes like those observed in MEFs that lack A- or B-type lamin isoforms. Finally, we demonstrate that the loss of each lamin isoform softens the cell nucleus and enhances constricted cell migration but in turn increases migration-induced DNA damage. Together, our findings uncover distinctive roles for each of the four major lamin isoforms in maintaining nucleocytoskeletal interactions and cellular mechanics.

Published
2022

2. Nuclear lamin isoforms differentially contribute to LINC complex-dependent nucleocytoskeletal coupling and whole-cell mechanics

Author

Massachusetts Institute of Technology. Department of Mechanical Engineering, Vahabikashi, Amir, Sivagurunathan, Suganya, Nicdao, Fiona Ann Sadsad, Han, Yu Long, Park, Chan Young, Kittisopikul, Mark, Wong, Xianrong, Tran, Joseph R, Gundersen, Gregg G, Reddy, Karen L, Luxton, GW Gant, Guo, Ming, Fredberg, Jeffrey J, Zheng, Yixian, Adam, Stephen A, Goldman, Robert D, Massachusetts Institute of Technology. Department of Mechanical Engineering, Vahabikashi, Amir, Sivagurunathan, Suganya, Nicdao, Fiona Ann Sadsad, Han, Yu Long, Park, Chan Young, Kittisopikul, Mark, Wong, Xianrong, Tran, Joseph R, Gundersen, Gregg G, Reddy, Karen L, Luxton, GW Gant, Guo, Ming, Fredberg, Jeffrey J, Zheng, Yixian, Adam, Stephen A, and Goldman, Robert D

Abstract

Significance Interactions between the cell nucleus and cytoskeleton regulate cell mechanics and are facilitated by the interplay between the nuclear lamina and linker of nucleoskeleton and cytoskeleton (LINC) complexes. To date, the specific contribution of the four lamin isoforms to nucleocytoskeletal connectivity and whole-cell mechanics remains unknown. We discover that A- and B-type lamins distinctively interact with LINC complexes that bind F-actin and vimentin filaments to differentially modulate cortical stiffness, cytoplasmic stiffness, and contractility of mouse embryonic fibroblasts (MEFs). We propose and experimentally verify an integrated lamin–LINC complex–cytoskeleton model that explains cellular mechanical phenotypes in lamin-deficient MEFs. Our findings uncover potential mechanisms for cellular defects in human laminopathies and many cancers associated with mutations or modifications in lamin isoforms.

Published
2023

3. Expression of vimentin alters cell mechanics, cell-cell adhesion, and gene expression profiles suggesting the induction of a hybrid EMT in human mammary epithelial cells

Author

Massachusetts Institute of Technology. Department of Mechanical Engineering, Sivagurunathan, Suganya, Vahabikashi, Amir, Yang, Haiqian, Zhang, Jun, Vazquez, Kelly, Rajasundaram, Dhivyaa, Politanska, Yuliya, Abdala-Valencia, Hiam, Notbohm, Jacob, Guo, Ming, Adam, Stephen A, Goldman, Robert D, Massachusetts Institute of Technology. Department of Mechanical Engineering, Sivagurunathan, Suganya, Vahabikashi, Amir, Yang, Haiqian, Zhang, Jun, Vazquez, Kelly, Rajasundaram, Dhivyaa, Politanska, Yuliya, Abdala-Valencia, Hiam, Notbohm, Jacob, Guo, Ming, Adam, Stephen A, and Goldman, Robert D

Abstract

Vimentin is a Type III intermediate filament (VIF) cytoskeletal protein that regulates the mechanical and migratory behavior of cells. Its expression is considered to be a marker for the epithelial to mesenchymal transition (EMT) that takes place in tumor metastasis. However, the molecular mechanisms regulated by the expression of vimentin in the EMT remain largely unexplored. We created MCF7 epithelial cell lines expressing vimentin from a cumate-inducible promoter to address this question. When vimentin expression was induced in these cells, extensive cytoplasmic VIF networks were assembled accompanied by changes in the organization of the endogenous keratin intermediate filament networks and disruption of desmosomes. Significant reductions in intercellular forces by the cells expressing VIFs were measured by quantitative monolayer traction force and stress microscopy. In contrast, laser trapping micro-rheology revealed that the cytoplasm of MCF7 cells expressing VIFs was stiffer than the uninduced cells. Vimentin expression activated transcription of genes involved in pathways responsible for cell migration and locomotion. Importantly, the EMT related transcription factor TWIST1 was upregulated only in wild type vimentin expressing cells and not in cells expressing a mutant non-polymerized form of vimentin, which only formed unit length filaments (ULF). Taken together, our results suggest that vimentin expression induces a hybrid EMT correlated with the upregulation of genes involved in cell migration.

Published
2023

4. Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Author

McDowell, Colleen M, McDowell, Colleen M, Kizhatil, Krishnakumar, Elliott, Michael H, Overby, Darryl R, van Batenburg-Sherwood, Joseph, Millar, J Cameron, Kuehn, Markus H, Zode, Gulab, Acott, Ted S, Anderson, Michael G, Bhattacharya, Sanjoy K, Bertrand, Jacques A, Borras, Terete, Bovenkamp, Diane E, Cheng, Lin, Danias, John, De Ieso, Michael Lucio, Du, Yiqin, Faralli, Jennifer A, Fuchshofer, Rudolf, Ganapathy, Preethi S, Gong, Haiyan, Herberg, Samuel, Hernandez, Humberto, Humphries, Peter, John, Simon WM, Kaufman, Paul L, Keller, Kate E, Kelley, Mary J, Kelly, Ruth A, Krizaj, David, Kumar, Ajay, Leonard, Brian C, Lieberman, Raquel L, Liton, Paloma, Liu, Yutao, Liu, Katy C, Lopez, Navita N, Mao, Weiming, Mavlyutov, Timur, McDonnell, Fiona, McLellan, Gillian J, Mzyk, Philip, Nartey, Andrews, Pasquale, Louis R, Patel, Gaurang C, Pattabiraman, Padmanabhan P, Peters, Donna M, Raghunathan, Vijaykrishna, Rao, Ponugoti Vasantha, Rayana, Naga, Raychaudhuri, Urmimala, Reina-Torres, Ester, Ren, Ruiyi, Rhee, Douglas, Chowdhury, Uttio Roy, Samples, John R, Samples, E Griffen, Sharif, Najam, Schuman, Joel S, Sheffield, Val C, Stevenson, Cooper H, Soundararajan, Avinash, Subramanian, Preeti, Sugali, Chenna Kesavulu, Sun, Yang, Toris, Carol B, Torrejon, Karen Y, Vahabikashi, Amir, Vranka, Janice A, Wang, Ting, Willoughby, Colin E, Xin, Chen, Yun, Hongmin, Zhang, Hao F, Fautsch, Michael P, Tamm, Ernst R, Clark, Abbot F, Ethier, C Ross, Stamer, W Daniel, McDowell, Colleen M, McDowell, Colleen M, Kizhatil, Krishnakumar, Elliott, Michael H, Overby, Darryl R, van Batenburg-Sherwood, Joseph, Millar, J Cameron, Kuehn, Markus H, Zode, Gulab, Acott, Ted S, Anderson, Michael G, Bhattacharya, Sanjoy K, Bertrand, Jacques A, Borras, Terete, Bovenkamp, Diane E, Cheng, Lin, Danias, John, De Ieso, Michael Lucio, Du, Yiqin, Faralli, Jennifer A, Fuchshofer, Rudolf, Ganapathy, Preethi S, Gong, Haiyan, Herberg, Samuel, Hernandez, Humberto, Humphries, Peter, John, Simon WM, Kaufman, Paul L, Keller, Kate E, Kelley, Mary J, Kelly, Ruth A, Krizaj, David, Kumar, Ajay, Leonard, Brian C, Lieberman, Raquel L, Liton, Paloma, Liu, Yutao, Liu, Katy C, Lopez, Navita N, Mao, Weiming, Mavlyutov, Timur, McDonnell, Fiona, McLellan, Gillian J, Mzyk, Philip, Nartey, Andrews, Pasquale, Louis R, Patel, Gaurang C, Pattabiraman, Padmanabhan P, Peters, Donna M, Raghunathan, Vijaykrishna, Rao, Ponugoti Vasantha, Rayana, Naga, Raychaudhuri, Urmimala, Reina-Torres, Ester, Ren, Ruiyi, Rhee, Douglas, Chowdhury, Uttio Roy, Samples, John R, Samples, E Griffen, Sharif, Najam, Schuman, Joel S, Sheffield, Val C, Stevenson, Cooper H, Soundararajan, Avinash, Subramanian, Preeti, Sugali, Chenna Kesavulu, Sun, Yang, Toris, Carol B, Torrejon, Karen Y, Vahabikashi, Amir, Vranka, Janice A, Wang, Ting, Willoughby, Colin E, Xin, Chen, Yun, Hongmin, Zhang, Hao F, Fautsch, Michael P, Tamm, Ernst R, Clark, Abbot F, Ethier, C Ross, and Stamer, W Daniel

Abstract

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Published
2022

5. Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Author

McDowell, Colleen M, McDowell, Colleen M, Kizhatil, Krishnakumar, Elliott, Michael H, Overby, Darryl R, van Batenburg-Sherwood, Joseph, Millar, J Cameron, Kuehn, Markus H, Zode, Gulab, Acott, Ted S, Anderson, Michael G, Bhattacharya, Sanjoy K, Bertrand, Jacques A, Borras, Terete, Bovenkamp, Diane E, Cheng, Lin, Danias, John, De Ieso, Michael Lucio, Du, Yiqin, Faralli, Jennifer A, Fuchshofer, Rudolf, Ganapathy, Preethi S, Gong, Haiyan, Herberg, Samuel, Hernandez, Humberto, Humphries, Peter, John, Simon WM, Kaufman, Paul L, Keller, Kate E, Kelley, Mary J, Kelly, Ruth A, Krizaj, David, Kumar, Ajay, Leonard, Brian C, Lieberman, Raquel L, Liton, Paloma, Liu, Yutao, Liu, Katy C, Lopez, Navita N, Mao, Weiming, Mavlyutov, Timur, McDonnell, Fiona, McLellan, Gillian J, Mzyk, Philip, Nartey, Andrews, Pasquale, Louis R, Patel, Gaurang C, Pattabiraman, Padmanabhan P, Peters, Donna M, Raghunathan, Vijaykrishna, Rao, Ponugoti Vasantha, Rayana, Naga, Raychaudhuri, Urmimala, Reina-Torres, Ester, Ren, Ruiyi, Rhee, Douglas, Chowdhury, Uttio Roy, Samples, John R, Samples, E Griffen, Sharif, Najam, Schuman, Joel S, Sheffield, Val C, Stevenson, Cooper H, Soundararajan, Avinash, Subramanian, Preeti, Sugali, Chenna Kesavulu, Sun, Yang, Toris, Carol B, Torrejon, Karen Y, Vahabikashi, Amir, Vranka, Janice A, Wang, Ting, Willoughby, Colin E, Xin, Chen, Yun, Hongmin, Zhang, Hao F, Fautsch, Michael P, Tamm, Ernst R, Clark, Abbot F, Ethier, C Ross, Stamer, W Daniel, McDowell, Colleen M, McDowell, Colleen M, Kizhatil, Krishnakumar, Elliott, Michael H, Overby, Darryl R, van Batenburg-Sherwood, Joseph, Millar, J Cameron, Kuehn, Markus H, Zode, Gulab, Acott, Ted S, Anderson, Michael G, Bhattacharya, Sanjoy K, Bertrand, Jacques A, Borras, Terete, Bovenkamp, Diane E, Cheng, Lin, Danias, John, De Ieso, Michael Lucio, Du, Yiqin, Faralli, Jennifer A, Fuchshofer, Rudolf, Ganapathy, Preethi S, Gong, Haiyan, Herberg, Samuel, Hernandez, Humberto, Humphries, Peter, John, Simon WM, Kaufman, Paul L, Keller, Kate E, Kelley, Mary J, Kelly, Ruth A, Krizaj, David, Kumar, Ajay, Leonard, Brian C, Lieberman, Raquel L, Liton, Paloma, Liu, Yutao, Liu, Katy C, Lopez, Navita N, Mao, Weiming, Mavlyutov, Timur, McDonnell, Fiona, McLellan, Gillian J, Mzyk, Philip, Nartey, Andrews, Pasquale, Louis R, Patel, Gaurang C, Pattabiraman, Padmanabhan P, Peters, Donna M, Raghunathan, Vijaykrishna, Rao, Ponugoti Vasantha, Rayana, Naga, Raychaudhuri, Urmimala, Reina-Torres, Ester, Ren, Ruiyi, Rhee, Douglas, Chowdhury, Uttio Roy, Samples, John R, Samples, E Griffen, Sharif, Najam, Schuman, Joel S, Sheffield, Val C, Stevenson, Cooper H, Soundararajan, Avinash, Subramanian, Preeti, Sugali, Chenna Kesavulu, Sun, Yang, Toris, Carol B, Torrejon, Karen Y, Vahabikashi, Amir, Vranka, Janice A, Wang, Ting, Willoughby, Colin E, Xin, Chen, Yun, Hongmin, Zhang, Hao F, Fautsch, Michael P, Tamm, Ernst R, Clark, Abbot F, Ethier, C Ross, and Stamer, W Daniel

Abstract

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Published
2022

6. Nuclear lamins: Structure and function in mechanobiology

Author

Vahabikashi, Amir; https://orcid.org/0000-0002-5713-0231, Adam, Stephen A, Medalia, Ohad; https://orcid.org/0000-0003-0994-2937, Goldman, Robert D, Vahabikashi, Amir; https://orcid.org/0000-0002-5713-0231, Adam, Stephen A, Medalia, Ohad; https://orcid.org/0000-0003-0994-2937, and Goldman, Robert D

Abstract

Nuclear lamins are type V intermediate filament proteins that polymerize into complex filamentous meshworks at the nuclear periphery and in less structured forms throughout the nucleoplasm. Lamins interact with a wide range of nuclear proteins and are involved in numerous nuclear and cellular functions. Within the nucleus, they play roles in chromatin organization and gene regulation, nuclear shape, size, and mechanics, and the organization and anchorage of nuclear pore complexes. At the whole cell level, they are involved in the organization of the cytoskeleton, cell motility, and mechanotransduction. The expression of different lamin isoforms has been associated with developmental progression, differentiation, and tissue-specific functions. Mutations in lamins and their binding proteins result in over 15 distinct human diseases, referred to as laminopathies. The laminopathies include muscular (e.g., Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy), neurological (e.g., microcephaly), and metabolic (e.g., familial partial lipodystrophy) disorders as well as premature aging diseases (e.g., Hutchinson-Gilford Progeria and Werner syndromes). How lamins contribute to the etiology of laminopathies is still unknown. In this review article, we summarize major recent findings on the structure, organization, and multiple functions of lamins in nuclear and more global cellular processes.

Published
2022

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