Intracellular enhancement of BMP signaling by LIM-domain protein FHL3 controls spatiotemporal emergence of the neural crest driven by WNT signaling

How multiple morphogen signals are coordinated in space and time to position key embryonic tissues remains elusive. During neural crest formation, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and WNT signaling cooperate by acting either on the paraxial mesoderm or directly on the neural border ectoderm, but how each tissue interprets this complex information remains poorly understood. Here we show that Fhl3, a scaffold LIM domain protein of previously unknown developmental function, is essential for neural crest formation by linking BMP and WNT signaling thereby positioning the neural crest-inducing signaling center in the paraxial mesoderm. During gastrulation, Fhl3 promotes Smad phosphorylation and Smad-dependent wnt8 activation specifically in the paraxial mesoderm, thus modifying the respective mesoderm or ectoderm cell response to the extracellular BMP gradient. This ensures neural border ectoderm specification by the underlying mesoderm via non-cell autonomous WNT signaling. During neurulation, neural crest inducers activate fhl3, promoting BMP/Smad-dependent WNT activity required for neural crest specification. Our findings highlight how Fhl3, acting cell-autonomously, ensures a fine spatial, temporal and germ layer-specific coordination of BMP and WNT signaling at several steps of neural crest development.Highlights:-FHL3 is a novel intracellular enhancer of BMP signaling during early development.-FHL3 ensures cross-talk between BMP and WNT signaling by Smad1-dependent wnt8 activation in the paraxial mesoderm.-FHL3 reiterated function in paraxial mesoderm and in neural border ectoderm is essential for neural crest development at the border of the neural plate.