FGF8 Acts as a Right Determinant during Establishment of the Left-Right Axis in the Rabbit

BACKGROUND FGF8 has been implicated in the transfer of left-right (L-R) asymmetry from the embryonic midline (node) to the lateral plate mesoderm (LPM). Surprisingly, opposite roles have been described in chick and mouse. In mouse, FGF8 is required for the left-asymmetric expression of nodal, lefty2, and Pitx2. In chick, FGF8 represses nodal and Pitx2 on the right side. This discrepancy could reflect evolutionary differences between birds and mammals. Alternatively, the right-asymmetric expression of fgf8, which is not found in mouse, at the chick node may be a prerequisite of right-sided function. Finally, chick (blastodisc) and mouse (egg cylinder) differ with respect to the topology of the early gastrula/neurula embryo. RESULTS The rabbit blastodisc was investigated as an additional mammalian L-R model system. While nodal, lefty, and Pitx2 showed asymmetric expression in the left LPM, fgf8 and all other midline marker genes were symmetrically expressed at the node like in mouse. Left-sided application of FGF8 repressed the endogenous transcription of nodal as well as ectopic expression induced by the parallel administration of BMP4. Right-sided inhibition of FGF8 signaling induced bilateral marker gene expression, demonstrating that, in rabbit, FGF8 acts as a right determinant like in chick. CONCLUSIONS These findings suggest that the anatomy of the early embryo (blastodisc versus egg cylinder) rather than taxonomical differences or asymmetry in expression constitutes an important determinant of FGF8 function in L-R axis formation. The rabbit may provide a useful model for early human embryogenesis, as human embryos develop via a blastodisc as well.