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Nat Commun 2024 Feb 02;151:1003. doi: 10.1038/s41467-024-44951-7.
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R-Spondin 2 governs Xenopus left-right body axis formation by establishing an FGF signaling gradient.

Lee H , Camuto CM , Niehrs C .

Establishment of the left-right (LR, sinistral, dextral) body axis in many vertebrate embryos relies on cilia-driven leftward fluid flow within an LR organizer (LRO). A cardinal question is how leftward flow triggers symmetry breakage. The chemosensation model posits that ciliary flow enriches a signaling molecule on the left side of the LRO that promotes sinistral cell fate. However, the nature of this sinistralizing signal has remained elusive. In the Xenopus LRO, we identified the stem cell growth factor R-Spondin 2 (Rspo2) as a symmetrically expressed, sinistralizing signal. As predicted for a flow-mediated signal, Rspo2 operates downstream of leftward flow but upstream of the asymmetrically expressed gene dand5. Unexpectedly, in LR patterning, Rspo2 acts as an FGF receptor antagonist: Rspo2 via its TSP1 domain binds Fgfr4 and promotes its membrane clearance by Znrf3-mediated endocytosis. Concordantly, we find that at flow-stage, FGF signaling is dextralizing and forms a gradient across the LRO, high on the dextral- and low on the sinistral side. Rspo2 gain- and loss-of function equalize this FGF signaling gradient and sinistralize and dextralize development, respectively. We propose that leftward flow of Rspo2 produces an FGF signaling gradient that governs LR-symmetry breakage.

PubMed ID: 38307837
PMC ID: PMC10837206
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: babam2 bmp4 cltc ctnnb1 dand5 dkk1 eea1 egf elk1 fgf19 fgf23 fgfr1 fgfr4 furin lamp1 lgr4 lrp6 mapk1 nodal nog pitx2 rnf43 rspo1 rspo2 rspo3 smad1 stom szl tf wnt3a znrf3
Morpholinos: lrp6 MO1 rspo2 MO2 znrf3 MO2

Phenotypes: Xla Wt + rspo2 MO (Fig. 1 eg) [+]

Article Images: [+] show captions