The Short Stature Homeobox 2 (Shox2)-bone Morphogenetic Protein (BMP) Pathway Regulates Dorsal Mesenchymal Protrusion Development and Its Temporary Function as a Pacemaker during Cardiogenesis

Sun, Cheng; Yu, Diankun; Ye, Wenduo; Liu, Chao; Gu, Shaohua; Sinsheimer, Nathan R.; Song, Zhongchen; Li, Xihai; Chen, Chun; Song, Yingnan; Wang, Shusheng; Schrader, Laura A.; Chen, Yiping

doi:10.1074/jbc.m114.619007

Cited by 28 publications

(40 citation statements)

References 51 publications

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“…AVJ develops from the dorsal mesenchymal protrusion, cushion septum tissues and the AVC-originating myocardium, including AVN progenitor cells (Munshi 2012;Ionta et al 2015). In contrast to the previous opinion that Shox2 expression is specifically distributed in the SAN and its precursor tissues, Shox2 is also expressed in the dorsal mesenchymal protrusion tissues and AVJ during embryonic development (Sun et al 2015). Pacemaker cell-specific expression levels of Hcn4 and Tbx3 genes and SAN-like electrophysiological characteristics have been identified in the Shox2 + dorsal mesenchymal protrusion tissues and gradually disappear with the maturation of the AVN.…”

Section: The Effect Of the Shox2 Gene In The Atrioventricular Conductcontrasting

confidence: 46%

“…Until E11.5, the Shox2 gene-expressing region expands to two parallel fascicular zones crossing the atrium vertical axis formed by SAN and venous valves, and these regions will constitute an indivisible part of CCS later. Simultaneously, Shox2 is expressed in the mouse AVJ and the upper part of ventricles, forming the left and right bundle branches (Sun et al 2015) (Fig. 3).…”

Section: The Shox2 Gene and Distribution Of Its Expressionmentioning

confidence: 99%

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Shox2: The Role in Differentiation and Development of Cardiac Conduction System

Xin

Zhao

et al. 2018

Tohoku J. Exp. Med.

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The formation and conduction of electrocardiosignals and the synchronous contraction of atria and ventricles with rhythmicity are both triggered and regulated by the cardiac conduction system (CCS). Defect of this system will lead to various types of cardiac arrhythmias. In recent years, the research progress of molecular genetics and developmental biology revealed a clearer understanding of differentiation and development of the cardiac conduction system and their regulatory mechanisms. Short stature homeobox 2 (Shox2) transcription factor, encoded by Shox2 gene in the mouse, is crucial in the formation and differentiation of the sinoatrial node (SAN). Shox2 drives embryonic development processes and is widely expressed in the appendicular skeleton, palate, temporomandibular joints, and heart. Mutations of Shox2 can lead to dysembryoplasia and abnormal phenotypes, including bradycardiac arrhythmia. In this review, we provide a summary of the latest research progress on the regulatory effects of the Shox2 gene in differentiation and development processes of the cardiac conduction system, hoping to deepen the knowledge and understanding of this systematic process based on the cardiac conduction system. Overall, the Shox2 gene is intimately involved in the differentiation and development of cardiac conduction system, especially sinoatrial node. We also summarize the current information about human SHOX2. This review article provides a new direction in biological pacemaker therapies.

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Section: The Effect Of the Shox2 Gene In The Atrioventricular Conductcontrasting

confidence: 46%

Section: The Shox2 Gene and Distribution Of Its Expressionmentioning

confidence: 99%

Shox2: The Role in Differentiation and Development of Cardiac Conduction System

Xin

Zhao

et al. 2018

Tohoku J. Exp. Med.

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“…Studies revealed that the SHOX gene regulates main body structure development in the early embryo, especially the development and maturation of limb skeleton [27][28][29][30][31]. Recent evidence suggested that the SHOX gene plays important roles in the development of the sinus venosus and sinoatrial node (SAN) and is, therefore, crucial for the formation of the cardiac autonomic rhythm system [32][33][34]. In addition, it was also suggested that the SHOX gene is related to mechanosensory and palate development [35,36].…”

Section: The Function Of Shoxgenementioning

confidence: 97%

Diagnosis of Lung Cancer by SHOX2 Gene Methylation Assay

Song

Yu²,

Li³

2015

Mol Diagn Ther

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Lung cancer is the most prevalent cancer in the world. Few effective and cheap methods are available so far for early detection and screening of lung cancer. Although histological and cytological examinations are gold standards in lung cancer diagnosis, patients are always at late stages when diagnosis is confirmed. Therefore, new diagnostic methods are needed urgently to increase the early diagnostic rate, enhance the confirmed diagnostic rate, and reduce mortality. The SHOX2 gene methylation assay has become a promising option for the above purposes. It has been shown to enhance the confirmed diagnostic rate of lung cancer in several clinical trials when combined with histological or cytological assays, and has the potential to become an early diagnostic tool. This article reviews the outcome of clinical trials using the SHOX2 gene methylation assay alone or in combination with other examinations, and suggests its future applications and research directions.

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“…1) (2). To differentiate between the DMP prior to muscularization (which occurs from approximately embryonic day (E)13 in mouse) and other structures in the AV junction (AVJ) during early development, stainings of myocardial markers are essential, which are lacking in the paper by Sun et al (1). In our opinion, the 3 and 4).…”

mentioning

confidence: 97%

“…Sun et al (1) report that the dorsal mesenchymal protrusion (DMP) acts as a temporary pacemaker during early development, prior to formation of the atrioventricular node (AVN). We would like to question whether the anatomical designation of the DMP used in this paper is correct.…”

mentioning

confidence: 99%

Does the Dorsal Mesenchymal Protrusion Act as a Temporary Pacemaker during Heart Development?

Kelder

Vicente‐Steijn

DeRuiter

et al. 2015

Journal of Biological Chemistry

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Sun et al. (1) report that the dorsal mesenchymal protrusion (DMP) acts as a temporary pacemaker during early development, prior to formation of the atrioventricular node (AVN). We would like to question whether the anatomical designation of the DMP used in this paper is correct.The DMP was originally described as a mesenchymal protrusion from the dorsal mesocardium toward the atrial cavity contributing to the base of the atrial septum along with the mesenchymal cap and AV cushions (see Fig. 1) (2). To differentiate between the DMP prior to muscularization (which occurs from approximately embryonic day (E)13 in mouse) and other structures in the AV junction (AVJ) during early development, stainings of myocardial markers are essential, which are lacking in the paper by Sun et al. (1). In our opinion, the 3 and 4). HCN4 expression to date has not been described in mesenchyme (3-5). Co-expression of HCN4/TBX3 in cells in the AVJ, with nodal-like electrophysiological characteristics (1) corresponds to the (putative) AVN region instead of the DMP, which is in accordance with our own observations (4). Misnaming the DMP during early development leads to the erroneous conclusion that this structure shows pacemaking properties.Although we do not support the conclusion that the DMP acts as a temporary pacemaker, the results described by Sun et al.(1) elegantly show an important role for the Shox2-BMP pathway during AVN development. Tim P. Kelder

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The Short Stature Homeobox 2 (Shox2)-bone Morphogenetic Protein (BMP) Pathway Regulates Dorsal Mesenchymal Protrusion Development and Its Temporary Function as a Pacemaker during Cardiogenesis

Cited by 28 publications

References 51 publications

Shox2: The Role in Differentiation and Development of Cardiac Conduction System

Shox2: The Role in Differentiation and Development of Cardiac Conduction System

Diagnosis of Lung Cancer by SHOX2 Gene Methylation Assay

Does the Dorsal Mesenchymal Protrusion Act as a Temporary Pacemaker during Heart Development?

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