Interplay of cell–cell contacts and RhoA/
            <scp>MRTF</scp>
            ‐A signaling regulates cardiomyocyte identity

Dorn, Tatjana; Kornherr, Jessica; Parrotta, Elvira Immacolata; Zawada, Dorota; Ayetey, Harold; Santamaria, Gianluca; Iop, Laura; Mastantuono, Elisa; Sinnecker, Daniel; Goedel, Alexander; Dirschinger, Ralf J.; My, Ilaria; Laue, Svenja; Bozoglu, Tarik; Baarlink, Christian; Ziegler, Tilman; Graf, Elisabeth; Hinkel, Rabea; Cuda, Giovanni; Kääb, Stefan; Grace, Andrew A.; Grosse, Robert; Kupatt, Christian; Meitinger, Thomas; Smith, Austin; Laugwitz, Karl‐Ludwig; Moretti, Alessandra

doi:10.15252/embj.201798133

Cited by 68 publications

(69 citation statements)

References 75 publications

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“…51 Because cell shape change is facilitated by disruption of the actin cytoskeleton, this disruption is required for all white, brown, and beige adipocyte differentiation 52 ; some recent studies indicated that the inhibition of RhoA and ROCK-mediated actin cytoskeleton dynamics is required for all three types of adipogenesis. 31,39,40 Our observations in this study provide direct support for a negative role of ROCK2 activity in beige adipogenesis in vivo and in vitro, accordingly linking ROCK2 with previously known RhoA/ ROCK upstream and downstream signaling pathways; we therefore further recognize the important metabolic impacts of ROCK2 in obesity. The other result noteworthy is that we found an inverse relationship between ROCK2 activity (and total ROCK activity) and the abundance of brown/beige adipocytes in fat depots (Figure 2; Figure S2), further supports the notion that ROCK2 activity inhibits beige adipogenesis through promoting actin cytoskeleton dynamics.…”

Section: Discussionsupporting

confidence: 72%

“…[24][25][26][27] In addition, increased actin stress fiber formation facilitates nuclear translocation of MRTF-A, which is a transcriptional cofactor of serum response factor leading to increased actin cytoskeleton gene expression and decreased PPARγ activity. 31,39,40 Our observations in this study provide direct support for a negative role of ROCK2 activity in beige adipogenesis in vivo and in vitro, accordingly linking ROCK2 with previously known RhoA/ F I G U R E 8 Schematic summary of roles of ROCK2 activity in regulating adipogenesis, obesity, and insulin resistance. 51 Because cell shape change is facilitated by disruption of the actin cytoskeleton, this disruption is required for all white, brown, and beige adipocyte differentiation 52 ; some recent studies indicated that the inhibition of RhoA and ROCK-mediated actin cytoskeleton dynamics is required for all three types of adipogenesis.…”

Section: Discussionsupporting

confidence: 70%

“…Increased evidence supports that actin cytoskeleton remodeling plays an important role in brown/beige adipogenesis, 31,39,40 while the contribution of ROCK isoforms in vivo has never been elucidated. In this study, we investigated in vivo and in vitro roles of ROCK2 in beige adipogenesis, obesity, and insulin resistance using both ROCK2 +/− and ROCK2 +/KD mouse models, the latter harboring a ROCK2 allele with a kinase-dead (KD) mutation.…”

Section: Introductionmentioning

confidence: 99%

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ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

et al. 2019

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The RhoA/ROCK‐mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological, and metabolic analyses in ROCK2+/− and ROCK2+/KD mouse models, the latter harboring an allele with a kinase‐dead (KD) mutation. Both ROCK2+/− and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/− mice on a high‐fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/− stromal‐vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro‐beige phenotype of ROCK2+/− SV cells. In conclusion, ROCK2 activity‐mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age‐related and diet‐induced fat mass gain and insulin resistance.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

et al. 2019

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“…Inactivating Pitx2 in postnatal cardiomyocytes that are regenerating caused accumulation of adipose-like cells within the myocardium, similar to the phenotype that is observed in ARVC patients. The pathological adipose tissue that is found in ARVC patients is thought to be derived from cardiomyocytes of the second heart field and/or bi-potent Isl1 + Wt1 + cell populations (Dorn et al, 2018;Lombardi et al, 2009). In contrast, genetic lineage tracing with the mTmG double-fluorescent Cre reporter of Pitx2 CKO animals injured at P2 showed that the fat cells were of non-myocyte origin.…”

Section: Discussionmentioning

confidence: 99%

Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition

Tao

Hill

et al. 2018

Development

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Loss of the paired-like homeodomain transcription factor 2 (Pitx2) in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity. In addition, Pitx2 gain-of-function protects mature cardiomyocytes from ischemic injury and promotes heart repair. Here, we characterized the longterm myocardial phenotype following myocardial infarction (MI) in Pitx2 conditional-knockout (Pitx2 CKO) mice. We found adipose-like tissue in Pitx2 CKO hearts 60 days after MI induced surgically at postnatal day 2 but not at day 8. Molecular and cellular analyses showed the onset of adipogenic signaling in mutant hearts after MI. Lineage tracing experiments showed a non-cardiomyocyte origin of the de novo adipose-like tissue. Interestingly, we found that Pitx2 promotes mitochondrial function through its gene regulatory network, and that the knockdown of a key mitochondrial Pitx2 target gene, Cox7c, also leads to the accumulation of myocardial fat tissue. Single-nuclei RNA-seq revealed that Pitx2-deficient hearts were oxidatively stressed. Our findings reveal a role for Pitx2 in maintaining proper cardiac cellular composition during heart regeneration via the maintenance of proper mitochondrial structure and function.

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“…Moreover, dynamic assembly and disassembly of microfilaments (filamentous (F)-Actin) from G-actin monomers is generally important in cell integrity and control of mobility (31) and specifically important for the establishment of a circumferential F-actin belt parallel to the cell-cell contact area (32). Such microfilament structure is regulated by RhoA GTPase to control membrane rigidity and prevent anchorage detachment (33,34). We found that RhoA activity was decreased upon DSG2 suppression but increased when DSG2 was ectopically expressed (SI Appendix, Fig.…”

Section: Dsg2 Expression Promotes Metastatic Colonization and Tumor Gmentioning

confidence: 99%

Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer

Chang

Chen

Tsai

et al. 2019

Preprint

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AbstractMetastasis is the major cause of cancer death. Metastatic cancer cells that have intravasated into the circulatory system and formed clusters of circulating tumor cells (CTCs) are particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and CTC clustering remain elusive. We found that high expression of Desmoglein2 (DSG2), a cell adhesion molecule involved in desmosome mediated intercellular adhesion, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process as downregulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress allowed CTCs to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis.Significant StatementDuring metastasis, a hypoxic microenvironment is a major force driving primary tumor cells to disseminate into the circulatory system. The majority of these circulating tumor cells (CTCs) cannot survive when traveling alone. However, collective movement as CTC clusters enables them to avoid immune surveillance and increases the probability that they will successfully metastasize to distal organs. Dynamic down regulation of DSG2 in hypoxic tumor tissue and reactivation of expression in CTCs allowed high rates of tumor cell dissemination, CTC cluster formation and metastasis that are characteristics of the most aggressive breast cancers. The findings highlight both the potential, and potential pitfalls, of using DSG2 as a therapeutic target.

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Interplay of cell–cell contacts and RhoA/ MRTF ‐A signaling regulates cardiomyocyte identity

Cited by 68 publications

References 75 publications

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition

Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer

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