Natural reversal of cavefish heart asymmetry is controlled by Sonic Hedgehog effects on the left-right organizer

The direction of left-right (L-R) visceral asymmetry is conserved in vertebrates. Deviations of the asymmetric pattern are rare, and the underlying mechanisms are not understood. Here we use the teleost Astyanax mexicanus , a single species consisting of surface fish with normal left-oriented heart asymmetry and cavefish with high levels of reversed right-oriented heart asymmetry, to explore natural changes in L-R determination. We show that Sonic Hedgehog (Shh) signaling is increased at the posterior midline, Kupffers Vesicle (KV), the teleost L-R Organizer (LRO), is enlarged and contains longer cilia, and the number of dorsal forerunner cells, the KV precursors, is increased in cavefish. Furthermore, Shh overexpression in surface fish induces KV modifications and changes in heart asymmetry resembling the cavefish phenotype. Asymmetric expression of the Nodal antagonist dand5 is equalized or reversed in the cavefish KV, and Shh overexpression in surface fish mimics changes in cavefish L-R dand5 asymmetry and shifts Nodal laterality in the lateral plate mesoderm. Our results show that naturally occurring modifications in cavefish heart asymmetry are controlled by the effects of enhanced Shh signaling on LRO function. Summary Natural reversal of cavefish heart asymmetry is controlled by enhanced Sonic Hedgehog signaling at the posterior midline, which modifies left-right organizer function and subsequent Nodal laterality.