Evolutionary History of Hedgehog Signaling Genes and Smoothened Dose Sensitivity in Teleosts
摘要
The hedgehog signaling pathway is critical for normal development in all vertebrates, including teleost fishes such as zebrafish (Danio rerio), a commonly used model organism for development. Smoothened (smo) is a gatekeeper for downstream hedgehog signaling and therefore may be under selective pressure during body plan diversification. We have found evidence that mutations in smo have contributed to body plan diversification of teleosts, and in at least one case of cartilaginous fishes, during evolutionary history. Diversifying selection has acted primarily on the extracellular signal peptide and intracellular regions of Smo, consistent with evolution through dosage-dependent mechanisms. Repeated and independent selection events on smo have preceded species radiations in teleost lineages characterized by highly variable body elongation and head shape phenotypes. Zebrafish deficient in smo exhibit a variety of severe morphological defects that are incompatible with life beyond five days post fertilization, but a single functional allele of smo is sufficient for survival. Thus far, smo+/− zebrafish have been considered phenotypically indistinguishable from smo+/+ zebrafish, suggesting negligible effects of lower smo gene dosage. Despite that, we have identified subtle phenotypic changes in smo+/− zebrafish that suggest reduced gene activity has consequences. Taken together, these data suggest that the evolutionary flexibility of smo has created a permissive genetic environment for body plan modifications across diverse teleost fishes. Our results show that even partial loss of smo leads to measurable developmental changes in zebrafish, highlighting the dosage sensitivity of hedgehog signaling. Evolutionary analysis further supports this finding, revealing that smo has been retained as a single-copy gene across teleosts, suggesting strong selective pressure to maintain precise gene dosage.