Abstract
Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1−/− mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1−/− mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.
Highlights
Heart development is a complex process involving different cell types as well as different types of cell movements
The spatiotemporal expression of Smad ubiquitin regulatory factor 1 (SMURF1) during human heart development suggests that SMURF1 plays a role in multiple aspects of heart development, including outflow tract (OFT) septation and formation of smooth muscle cells (SMCs) in great and coronary arteries
In SMURF1-dependent EMT/endothelial to mesenchymal transition (EndoMT), TGFβ or bone morphogenetic protein (BMP) receptors reside at tight junctions in polarized epithelial/endothelial cells
Summary
Heart development is a complex process involving different cell types as well as different types of cell movements. SMURF proteins have been implicated in the positive and negative regulation of numerous cellular and developmentally important signaling pathways, including canonical TGFβ/BMP signaling as well as WNT/PCP signaling, TGFβ/PAR6/RHOA, Hedgehog, Hippo and NF-κB signaling[9,12,13,16,17,18,19,23,24,25,26,27] The majority of these pathways are known to be coordinated, at least in part, by the primary cilium - a microtubule-based signaling organelle that emerges from the surface of many different cell types in the body depending on their cell cycle and differentiation status[28,29,30,31,32,33,34]. These results provide important new insight into the process of OFT septation and the mechanisms that define cell-type specifications during cardiac development, in turn paving the way for improved in vitro differentiation of cardiomyocyte subtypes for use in treatment of cardiovascular diseases
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