Smad1 transcription factor integrates BMP2 and Wnt3a signals in migrating cardiac progenitor cells

Abstract

In vertebrate embryos, cardiac progenitor cells (CPCs) undergo long-range migration after emerging from the primitive streak during gastrulation. Together with other mesoderm progenitors, they migrate laterally and then toward the ventral midline, where they form the heart. Signals controlling the migration of different progenitor cell populations during gastrulation are poorly understood. Several pathways are involved in the epithelialto-mesenchymal transition and ingression of mesoderm cells through the primitive streak, including fibroblast growth factors and wingless-type family members (Wnt). Here we focus on early CPC migration and use live video microscopy in chicken embryos to demonstrate a role for bone morphogenetic protein (BMP)/SMA and MAD related (Smad) signaling. We identify an interaction of BMP and Wnt/glycogen synthase kinase 3 beta (GSK3β) pathways via the differential phosphorylation of Smad1. Increased BMP2 activity altered migration trajectories of prospective cardiac cells and resulted in their lateral displacement and ectopic differentiation, as they failed to reach the ventral midline. Constitutively active BMP receptors or constitutively active Smad1 mimicked this phenotype, suggesting a cell autonomous response. Expression of GSK3β, which promotes the turnover of active Smad1, rescued the BMP-induced migration phenotype. Conversely, expression of GSK3β-resistant Smad1 resulted in aberrant CPC migration trajectories. Derepression of GSK3β by dominant negative Wnt3a restored normal migration patterns in the presence of high BMP activity. The data indicate the convergence of BMP and Wnt pathways on Smad1 during the early migration of prospective cardiac cells. Overall, we reveal molecular mechanisms that contribute to the emerging paradigm of signaling pathway integration in embryo development.live imaging | cell tracking

Bmp2 conditional knockout in osteoblasts and endothelial cells does not impair bone formation after injury or mechanical loading in adult mice

“…However, our interpretation of the available evidence is that paracrine BMP2 effects are not likely, and chondrocyte BMP2 would not significantly affect knockout cells. First, developmental studies have shown that BMP2 on its own does not have a large effect radius [40–43]. Only cells within a 500um radius of a BMP2 eluting bead or cells modified to constitutively release BMP2 show phosphorylated SMAD activity or abnormal behavior [40,41,43].…”

“…First, developmental studies have shown that BMP2 on its own does not have a large effect radius [40–43]. Only cells within a 500um radius of a BMP2 eluting bead or cells modified to constitutively release BMP2 show phosphorylated SMAD activity or abnormal behavior [40,41,43]. Also, any matrix-bound BMP2 liberated following fracture is not sufficient to rescue healing when cells are not capable of producing adequate BMP2 as shown by the global knockouts used here (UBC-Cre) and by Wang et al [21].…”

The advancement of human pluripotent stem cell-derived therapies into the clinic

“…For this trial, the I6 hESC line is expanded on a feeder layer of clinical-grade human fibroblasts and differentiated using bone morphogenetic protein (BMP)-2 and the FGF receptor kinase inhibitor SU-5402 for 4 days (Menasché et al, 2014). BMP-2 and the closely related TGF-β superfamily member BMP-4 are important regulators of mesoderm formation and cardiogenesis (Winnier et al, 1995;Schultheiss et al, 1997;Song et al, 2014;Luo et al, 2015). Inhibition of FGF signaling was observed to improve the efficiency of cardiac differentiation mediated by BMP-2 (Tomescot et al, 2007).…”

WNT and BMP regulate roadblocks toward cardiomyocyte differentiation: lessons learned from embryos inform human stem cell differentiation

“…Their work is underpinned by numerous studies in developing vertebrate embryos, particularly in experimentally accessible model systems such as avian and amphibian, but also by genetic loss-offunction approaches in mice (20)(21)(22)(23). The characterization of a cardiac corridor for hESC differentiation suggests that there are gradients of Wnt and BMP signals that induce highly related but distinct cell fates, an idea which is indeed compatible with the expression of these signals and their inhibitors along the early embryonic axes (dorsoventral and anterior-posterior) [see examples (24)(25)(26)]. …”

“…Another aspect to consider is the finding that BMP/ Smad1 and Wnt/GSK3β cooperate to guide the early migration of cardiac progenitor cells as they emerge from the primitive streak (26). During embryogenesis, the processes controlling cell migration need to be coordinated with those that affect cell fate choice.…”