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.
Highlights
The mesodermal germ layer gives rise to a host of adult tissues and organs that constitute the musculoskeletal, cardiovascular, and genitourinary systems, among others
Using neuromesodermal progenitors (NMPs), we found that FGF induces medial fate through transcriptional activation of the basic helixloop-helix (bHLH) transcription factors myf5, myod, and msgn1, and BMP counters this and promotes lateral fate through transcriptional activation of Id genes
We examined the expression of bHLH transcription factors msgn1, myf5, and myod 6 hr after a 12-somite stage treatment with a MEK inhibitor. msgn1 expression is completely abolished, and there is a near complete loss of myf5 expression in MEK inhibited embryos (Figure 7A,B,D,E)
Summary
The mesodermal germ layer gives rise to a host of adult tissues and organs that constitute the musculoskeletal, cardiovascular, and genitourinary systems, among others. After mesoderm induction begins during vertebrate gastrulation, the germ layer is patterned by secreted morphogenetic signals that promote different mediolateral fates. Despite advances in determining how the BMP and FGF signaling gradients are established, the molecular mechanisms directing mediolateral pattern formation in the mesoderm remain unknown. Understanding patterning during gastrulation downstream of FGF and BMP signaling is complicated, since these pathways affect the patterning of the anterior-posterior (AP) axis (De Robertis, 2008; Kimelman, 2006). The pleiotropic patterning roles during gastrulation make it difficult to interpret their effects on specific mesodermal fate decisions at later stages of development. Interaction between the pathways further confounds a simple readout of their effects. FGF signaling represses transcriptional activation of BMP ligands, thereby inhibiting BMP
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