Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts

Abstract

Cardiac progenitor cells are multipotent and give rise to cardiac endothelium, smooth muscle, and cardiomyocytes. Here, we define and characterize the cardiomyoblast intermediate that is committed to the cardiomyocyte fate, and we characterize the niche signals that regulate commitment. Cardiomyoblasts express Hopx, which functions to coordinate local Bmp signals to inhibit the Wnt pathway, thus promoting cardiomyogenesis. Hopx integrates Bmp and Wnt signaling by physically interacting with activated Smads and repressing Wnt genes. The identification of the committed cardiomyoblast that retains proliferative potential will inform cardiac regenerative therapeutics. In addition, Bmp signals characterize adult stem cell niches in other tissues where Hopx-mediated inhibition of Wnt is likely to contribute to stem cell quiescence and to explain the role of Hopx as a tumor suppressor.

Wnt/β-catenin signaling enables developmental transitions during valvulogenesis

“…Therefore, we examined patterns of Wnt signaling activity using a lacZ knock-in allele of Axin2, a well-established universal Wnt target gene (Jho et al, 2002;Lustig et al, 2002). Corroborating previous reports (Gillers et al, 2015;Jain et al, 2015;Klaus et al, 2012), sections of X-gal-stained Axin2 lacZ/+ E9.5 embryos showed faint Axin2 expression in pOFT but not dOFT myocardium, the ventricular side of AVC myocardium and AVC mesenchyme ( Fig. 2A,B).…”

Notch-Wnt-Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner

“…Because the canonical Wnt pathway activates, rather than represses, transcription we hypothesize that Wnts regulate gene 'X' (Fig. 8), which in turn represses Bmp4 (Jain et al, 2015). The phenotype associated with Bmp inhibition alone (via dorsomorphin treatment) showed some similarities to Wnt activation on day 0, day 1 or day 3.…”

“…In some cases their interactions are synergistic (Basler et al, 1993;Galli et al, 2007;Hollyday et al, 1995;Lee et al, 1998). In others, Wnts and Bmps antagonize each other, creating countergradients across an organ (Baker et al, 1999;Jain et al, 2015;Theisen et al, 1996). Such crosstalk has not been examined in the cochlea.…”

cKit + cardiac progenitors of neural crest origin

“…These programs are activated sequentially, in parallel, or intersect to give rise to distinct heart domains. For example, the myocardial lineage originally develops from cardiac progenitors (CPs) of mesodermal origin (2)(3)(4)(5), which form the first and second heart fields. However, later during morphogenesis, the cardiomyogenic program diverges and activates cardiomyocyte proliferation signals, along with CPs from the hemogenic endothelium, epicardial, cardiopulmonary, and cardiac neural crest (CNC) lineages, to produce new cardiomyocytes (1,(6)(7)(8)(9)(10)(11).…”

“…We induced cardiomyogenesis in iPSCs with either ascorbic acid (AA), which drives cardiogenesis partly via an intermediate differentiation stage into cKit + /Nkx2.5 + CPs (15, 41), or BMP antagonism, a signaling pathway that regulates the development of both mesodermal and NC lineages (Fig. 4A) (2,5,31,(42)(43)(44)(45)(46).…”