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 [Developmental Biology]

December 8th, 2014 by Sun, C., Yu, D., Ye, W., Liu, C., Gu, S., Sinsheimer, N. R., Song, Z., Li, X., Chen, C., Song, Y., Wang, S., Schrader, L., Chen, Y.

The atrioventricular (AV) junction plays a critical role in chamber septation and transmission of cardiac conduction pulses. It consists of structures that develop from embryonic dorsal mesenchymal protrusion (DMP) and embryonic AV canal. Despite extensive studies on AV junction development, the genetic regulation of DMP development remains poorly understood. In this study, we present evidence that Shox2 is expressed in the developing DMP. Intriguingly, this Shox2-expressing domain possesses a pacemaker specific genetic profile including Hcn4 and Tbx3. This genetic profile leads to nodal-like electrophysiological properties, which is gradually silenced as the AV node becomes matured. Phenotypic analyses of Shox2-/- mice revealed a hypoplastic and defectively differentiated DMP, likely attributed to increased apoptosis, accompanied by dramatically reduced expression of Bmp4 and Hcn4, ectopic activation of Cx40 and aberrant pattern of action potentials. Interestingly, conditional deletion of Bmp4 or inhibition of BMP signaling by overexpression of Noggin using a Shox2-Cre allele led to similar DMP hypoplasia and downregulation of Hcn4, while activation of a transgenic Bmp4 allele in Shox2-/- background attenuated DMP defects. Moreover, the lack of Hcn4 expression in the DMP of mice carrying Smad4 conditional deletion and direct binding of pSmad1/5/8 to the Hcn4 regulatory region further confirm the Shox2-BMP genetic cascade in the regulation of DMP development. Our results reveal that Shox2 regulates DMP fate and development by controlling BMP signaling through the Smad-dependent pathway to drive tissue growth and to induce Hcn4 expression, and suggest a temporal pacemaking function for the DMP during early cardiogenesis.
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