Smad4 regulates the nuclear translocation of Nkx2-5 in cardiac differentiation

Hu, Wen‐Yu; Dong, A.; Karasaki, Kohei; Sogabe, Shota; Okamoto, Daiki; Saigo, Masato; Ishida, Mari; Yoshizumi, Masao; Kokubo, Hiroki

doi:10.1038/s41598-021-82954-2

Cited by 7 publications

(6 citation statements)

References 37 publications

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“…We investigated an important signaling pathway regulated by SMAD proteins that has been reported to regulate cardiogenesis [20]. Activated SMAD proteins 1/5/8 relay signals from the cell membrane to the nucleus via the common mediator SMAD4, triggering the activation of cardiogenic transcription factors GATA4, NKX2.5, and MEF2C [20,[38][39][40]. In line with previous reports, we observed that the enhanced expressions of the CM markers NKX2.5, GATA4, and MEF2C could be explained by the upregulation of SMAD 1/5/8 phosphorylation (Figure 2E).…”

Section: Discussionmentioning

confidence: 99%

Bioactive Lipid O-cyclic phytosphingosine-1-phosphate Promotes Differentiation of Human Embryonic Stem Cells into Cardiomyocytes via ALK3/BMPR Signaling

Jang

Kim

Antao

et al. 2021

IJMS

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Adult human cardiomyocytes have an extremely limited proliferative capacity, which poses a great barrier to regenerative medicine and research. Human embryonic stem cells (hESCs) have been proposed as an alternative source to generate large numbers of clinical grade cardiomyocytes (CMs) that can have potential therapeutic applications to treat cardiac diseases. Previous studies have shown that bioactive lipids are involved in diverse cellular responses including cardiogenesis. In this study, we explored the novel function of the chemically synthesized bioactive lipid O-cyclic phytosphingosine-1-phosphate (cP1P) as an inducer of cardiac differentiation. Here, we identified cP1P as a novel factor that significantly enhances the differentiation potential of hESCs into cardiomyocytes. Treatment with cP1P augments the beating colony number and contracting area of CMs. Furthermore, we elucidated the molecular mechanism of cP1P regulating SMAD1/5/8 signaling via the ALK3/BMP receptor cascade during cardiac differentiation. Our result provides a new insight for cP1P usage to improve the quality of CM differentiation for regenerative therapies.

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Section: Discussionmentioning

confidence: 99%

Bioactive Lipid O-cyclic phytosphingosine-1-phosphate Promotes Differentiation of Human Embryonic Stem Cells into Cardiomyocytes via ALK3/BMPR Signaling

Jang

Kim

Antao

et al. 2021

IJMS

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“…Smad4 is thought to be involved in cardiac development because disruption of the Smad4 gene resulted in the downregulation of cardiac-specific genes in Sfrp5-expressing cells, which are primarily cardiac progenitor cells for the FHF. That may account for the hypoplastic heart tubes seen in Smad4-knockout embryos ( 66 ). Smad4 can regulate the cardiac-specific gene expression and nuclear localization of Nkx2.5 ( 67 ).…”

Section: Transcription Regulation Of Nkx25mentioning

confidence: 99%

“…The Nkx2.5 protein is then phosphorylated by CK2, forming a protein complex with Smad4. This complex also moves into the nucleus and controls the transcription of the Nkx2.5 gene, effectively regulating the expression of Nkx2.5 ( 66 ). The Smad4 protein plays a vital role in cardiac development and myocardial regeneration through this mechanism.…”

Section: Transcription Regulation Of Nkx25mentioning

confidence: 99%

Nkx2.5: a crucial regulator of cardiac development, regeneration and diseases

Cao,

Li,

Zhang

et al. 2023

Front. Cardiovasc. Med.

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Cardiomyocytes fail to regenerate after birth and respond to mitotic signals through cellular hypertrophy rather than cellular proliferation. Necrotic cardiomyocytes in the infarcted ventricular tissue are eventually replaced by fibroblasts, generating scar tissue. Cardiomyocyte loss causes localized systolic dysfunction. Therefore, achieving the regeneration of cardiomyocytes is of great significance for cardiac function and development. Heart development is a complex biological process. An integral cardiac developmental network plays a decisive role in the regeneration of cardiomyocytes. During this process, genetic epigenetic factors, transcription factors, signaling pathways and small RNAs are involved in regulating the developmental process of the heart. Cardiomyocyte-specific genes largely promote myocardial regeneration, among which the Nkx2.5 transcription factor is one of the earliest markers of cardiac progenitor cells, and the loss or overexpression of Nkx2.5 affects cardiac development and is a promising candidate factor. Nkx2.5 affects the development and function of the heart through its multiple functional domains. However, until now, the specific mechanism of Nkx2.5 in cardiac development and regeneration is not been fully understood. Therefore, this article will review the molecular structure, function and interaction regulation of Nkx2.5 to provide a new direction for cardiac development and the treatment of heart regeneration.

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“…For example, Vincentz et al identified a direct interaction between NKX2-5 and MEF2C for ventricular chamber formation by influencing ventricular cardiomyocyte specification [82]. Cardiomyocyte differentiation promoted by NKX2-5 is regulated by BMP signaling via SMAD4, which controls not only the expression but also the nuclear localization of the transcription factor [83].…”

Section: Gene-gene and Gene-environment Interactions Involving Nkx2-5mentioning

confidence: 99%

Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review

2023

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Congenital heart defects (CHD) are the most common congenital abnormality, with an overall global birth prevalence of 9.41 per 1000 live births. The etiology of CHDs is complex and still poorly understood. Environmental factors account for about 10% of all cases, while the rest are likely explained by a genetic component that is still under intense research. Transcription factors and signaling molecules are promising candidates for studies regarding the genetic burden of CHDs. The present narrative review provides an overview of the current knowledge regarding some of the genetic mechanisms involved in the embryological development of the cardiovascular system. In addition, we reviewed the association between the genetic variation in transcription factors and signaling molecules involved in heart development, including TBX5, GATA4, NKX2-5 and CRELD1, and congenital heart defects, providing insight into the complex pathogenesis of this heterogeneous group of diseases. Further research is needed in order to uncover their downstream targets and the complex network of interactions with non-genetic risk factors for a better molecular–phenotype correlation.

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Smad4 regulates the nuclear translocation of Nkx2-5 in cardiac differentiation

Cited by 7 publications

References 37 publications

Bioactive Lipid O-cyclic phytosphingosine-1-phosphate Promotes Differentiation of Human Embryonic Stem Cells into Cardiomyocytes via ALK3/BMPR Signaling

Bioactive Lipid O-cyclic phytosphingosine-1-phosphate Promotes Differentiation of Human Embryonic Stem Cells into Cardiomyocytes via ALK3/BMPR Signaling

Nkx2.5: a crucial regulator of cardiac development, regeneration and diseases

Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review

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