Hedgehog Signaling Pathway - Evolution

Evolution

Hedgehog-like genes, 2 Patched homologs and Patched-related genes exist in the worm C. elegans. These genes have been shown to code for proteins that have roles in C. elegans development. The hedgehog-like and Patched-related gene families are very large and function without the need for a Smoothened homolog, suggesting a distinct pattern of selection for cholesterol modification and sensing mechanisms in coelomate and pseudo-coelomate lineages.

Lancelets, which are primitive chordates, possess only one homologue of Drosophila Hh (figure 7). Vertebrates, on the other hand, have several hedgehog ligands that fall within three subgroups - desert, Indian and sonic, each represented by a single mammalian gene. This is probably a consequence of the two genome duplications that occurred early in the vertebrate evolutionary history. Two such events would have produced four homologous genes, one of which must have been lost. Desert hedgehogs are the most closely related to Drosophila Hh. Additional gene duplications occurred within some species such as the zebrafish Danio rerio, which has an additional tiggywinkle hedgehog gene in the sonic group. Various vertebrate lineages have adapted hedgehogs to unique developmental processes. For example, a homologue of the X.laevis banded hedgehog is involved in regeneration of the salamander limb.

shh has undergone accelerated evolution in the primate lineage leading to humans. Dorus et al. hypothesise that this allowed for more complex regulation of the protein and may have played a role in the increase in volume and complexity of the human brain.

The frizzled family of WNT receptors have some sequence similarity to Smoothened. However, G proteins have been difficult to link to the function Smoothened. Smoothened seems to be a functionally divergent member of the G protein coupled receptor super family. Other similarities between the WNT and Hh signaling pathways have been reviewed. Nusse observed that, "a signaling system based on lipid-modified proteins and specific membrane translocators is ancient, and may have been the founder of the Wnt and Hh signaling systems".

It has been suggested that invertebrate and vertebrate signaling downstream from Smoothened has diverged significantly. The role of Suppressor of Fused (SUFU) has been enhanced in vertebrates compared to Drosophila where its role is relatively minor. Costal-2 is particularly important in Drosophila. The protein kinase Fused is a regulator of SUFU in Drosophila, but may not play a role in the Hh pathway of vertebrates. In vertebrates, Hh signaling has been heavily coupled to cilia

The hedgehog protein appears to have evolved in two sections, the N-terminal domain (hedge) and the C-terminal domain (hog), that only later were spliced together into a single transcriptional unit. The hedge domain contains a sequence called Hint (Hedgehog INTein), which is similar in sequence and function to bacterial and fungal inteins. Choanoflagellates contain a region named hoglet that is similar to the hedgehog C-terminal domain. In addition, molecular phylogenetic analysis revealed that hoglet was more similar to hog than it was to bacterial inteins. Choanoflagellates do not contain any regions similar to the hedge domain, suggesting that hog evolved first. Poriferans have both hedge-like proteins (termed hedgling) and hog-like proteins, but they exist as two completely separate transcriptional units. Cnidarians contain the hedgling and hog genes, but also have a complete hedgehog gene, indicating that hedge and hog were spliced into hedgehog after the last common ancestor of poriferans and cnidarians. Bilaterians do not contain hedgling genes, suggesting that these were lost by deletion before this branch split from the other metazoans.