BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity

Abstract

The mesodermal germ layer is patterned into mediolateral subtypes by signaling factors including BMP and FGF. How these pathways are integrated to induce specific mediolateral cell fates is not well understood. We used mesoderm derived from post-gastrulation neuromesodermal progenitors (NMPs), which undergo a binary mediolateral patterning decision, as a simplified model to understand how FGF acts together with BMP to impart mediolateral fate. Using zebrafish and mouse NMPs, we identify an evolutionarily conserved mechanism of BMP and FGF-mediated mediolateral mesodermal patterning that occurs through modulation of basic helix-loop-helix (bHLH) transcription factor activity. BMP imparts lateral fate through induction of Id helix loop helix (HLH) proteins, which antagonize bHLH transcription factors, induced by FGF signaling, that specify medial fate. We extend our analysis of zebrafish development to show that bHLH activity is responsible for the mediolateral patterning of the entire mesodermal germ layer.

Single-cell transcriptomic analysis identifies the conversion of zebrafish Etv2-deficient vascular progenitors into skeletal muscle

“…A recent study has demonstrated two opposing activities of FGF and BMP signaling in specifying somitic progenitors and the LPM 40 . FGF signaling through bHLH factors myf5, myod and msgn1 induced medial fate such as skeletal muscle in tailbudderived neuromesodermal progenitors while BMP signaling induced blood and endothelium marker expression, and etv2 expression in particular, through transcriptional activation of id genes, including id1 and id3.…”

“…FGF signaling through bHLH factors myf5, myod and msgn1 induced medial fate such as skeletal muscle in tailbudderived neuromesodermal progenitors while BMP signaling induced blood and endothelium marker expression, and etv2 expression in particular, through transcriptional activation of id genes, including id1 and id3. Loss of msgn1/myod/myf5 function or activation of hs:id3 expression resulted in a dramatic expansion of etv2 expression into the paraxial mesoderm 40 . Our results show that a loss of etv2 expression results in the opposite phenotype, and endothelial progenitors differentiate as skeletal muscle cells.…”

“…Based on scRNA-seq analysis, cell cluster #6 was significantly increased in etv2 ci32Gt−/− ; UAS:GFP embryos. Marker genes for this population included BMP response genes id3 and id1 (Supplementary Table 1, Supplementary Data 1), which have been recently shown to function upstream of etv2 during vascular differentiation of tailbud-derived neuromesodermal progenitors 40 . Another marker gene for this population, twist1a, has been implicated in developmental angiogenesis 41 , although its mechanistic role in this process has not been investigated.…”

Generation and characterization of cardiac valve endothelial-like cells from human pluripotent stem cells

“…BMP target genes ID1/2, MSX, TGFb2, TBX2 and TBX20 are known to be expressed in human valve endocardial cells and important for the endocardial cushion formation (Combs and Yutzey, 2009;Papoutsi et al, 2018;Shelton and Yutzey, 2007;Singh et al, 2011). Mechanistically, BMP signaling may function by promoting the earliest cardiac markers NKX2.5 and GATA4 as well as the earliest valve endothelial markers such as NFATc1, JAG1 and HEY1/2 (Bai et al, 2010;Row et al, 2018;Zhou et al, 2004;Wu et al, 2011).…”

Unraveling the Connection between Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling

“…Certainly, there are examples where downstream components of both pathways are (at least unilaterally) antagonizing, as exemplified in the inactivation of R-SMADs by Erk-mediated linker-phosphorylation, or in the inhibition of bHLH factors downstream of FGF2 by ID proteins downstream of BMP4 [ 107 ]. However, more often than not, BMP-FGF interaction is linked by intermediates operating on the level of transcription.…”