Embryonic morphogenesis of a complex organism requires proper regulation of patterning and directional growth. The Planar Cell Polarity (PCP) signaling is emerging as a critical evolutionarily conserved mechanism whereby directional information is conveyed. PCP is thought to be established by global cues, and recent studies have revealed an instructive role of Wnt signaling gradient in epithelia tissues of both invertebrates and vertebrates. However, it remains unclear whether Wnt/PCP signaling is coordinately regulated with embryonic patterning during morphogenesis. Here in the mammalian developing limbs, we find that the AER-derived Fgfs required for limb patterning regulates PCP along the proximal-distal axis in a Wnt5a-dependent manner. We demonstrate with genetic evidence that Wnt5a gradient acts as a global cue that is instructive in establishing PCP in the limb mesenchyme, while Wnt5a also plays a permissive role to allow Fgf signaling to orient PCP. Our results indicate that limb morphogenesis is critically regulated by coordination of directional growth and patterning through integrating Wnt5a and Fgf signaling in PCP regulation.
Coordinated directional outgrowth and pattern formation by integration of Wnt5a and Fgf signaling in planar cell polarity
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