Issue 8 Article 4

PB Fact Files #2: Sonic hedgehog protein

25/8/20

By:

Lee Zhe Yu, Nathan

Edited:

Elijah Chew Ze Feng

Tag:

Molecular Biology and Biochemistry

Welcome to the Project BioLogical Fact Files series, where we do a deep dive into an organism / biomolecule / virus. We hope that this series of articles allows you to gain a deeper appreciation about the biological diversity all around us, from the molecular level to the organisms that inhabit various ecosystems. After discussing the peculiarities of the Asari Clam (Ruditapes philippinarum), we now delve into a uniquely named protein, the Sonic hedgehog protein. While the name and its origin may seem frivolous, it plays a critical role in embryonic development, ensuring that we are able to function normally.

Firstly, why “Sonic hedgehog” of all names?

Famous geneticists Christiane Nüsslein-Volhard and Eric Wieschaus were analysing genetic mutations 45 years ago in 1980 when they noticed small hairs on fruit fly larvae curling up upon the deletion of a gene, giving the larvae a spiny, hedgehog-like appearance.

13 years later, a team of 3 collaborating laboratories led by Cliff Tabin, Andrew McMahon, and Philip Ingham identified 3 homologous genes across species that caused the abnormal segmentation as observed earlier. The 3 teams resolved to name each of the 3 genes after real hedgehog species in the world. To be fair, the latter two teams kept their end of the bargain, leading to the Desert hedgehog protein and Indian hedgehog protein. But, as always, one person had to rebel against the system, and that was to be Dr Tabin.

Dr Robert Riddle was working in Dr Tabin’s lab at that time, and noticed an advertisement for the game “Sonic the Hedgehog” in a magazine that his wife brought home. Thinking that it sounded similar to a band he followed called “Sonic Youth”, he suggested to Dr Tabin to name the protein “Sonic the Hedgehog” in a hidden reference to the band. Dr Tabin accepted Dr Riddle’s suggestion, and that was the name eventually published on the paper despite the consternations of Dr McMahon and Dr Ingham.

While the name was initially met with significant backlash from scientists due to its perceived frivolousness, the gene remains called Sonic Hedgehog (Shh) in scientific literature to this day rather than discounting the light-hearted side of scientists (who are, evidently, humans as well) and science as a whole.

However, the roles the Shh gene and its encoded protein play are far from frivolous, being crucial to normal animal development as part of the Hedgehog signalling pathway.

Chemical activity

The Shh protein precursor cleaves itself to form two proteins (ShhN and ShhC) before a cholesterol molecule is attached to the carbon-terminus (the carboxylic acid end) of the newly formed ShhN protein, which will become biologically active (i.e. ensure normal human development). The ShhC protein is then degraded at the rough endoplasmic reticulum (a membrane system in our cells responsible for protein degradation).

The zinc atom found in ShhN inhibits the addition of two lipid molecules to ShhN, preventing it from exhibiting any chemical activity. This prevents the overproduction of active ShhN, preventing abnormalities.

Biological Significance

The ShhN protein is an essential signalling molecule in the aptly named Hedgehog pathway, which controls the formation of almost all the organs in your body. The ShhN protein in particular controls the formation of the nervous system, helping to differentiate between the different cell types, including neurons.

ShhN also determines the spatial arrangement and development of limbs in animals. The latter implies that ShhN can control the appearance of animal limbs, which led to the famous observation of the curling of hairs on fruit fly larvae by Nüsslein-Volhard and Wieschaus that began this story.

Finally, ShhN also plays an important role in determining the front (anterior) and back (posterior) of animals.

With great power comes many problems

Its vital role in human development also implies that defects in the Shh gene (and by extension, the ShhN protein) have grave consequences for human health. Non-functional ShhN proteins have been linked with holoprosencephaly (HPE), where the animal brain fails to divide into the right and left hemisphere. This results in a single fused brain instead of the usual two halves that we see in typical animals, and manifests itself in facial deformities on the animals. (Caution: This also means that Google searches on HPE are likely to return highly graphic images, as our editor found out to his detriment) Shh gene defects have also been linked to VACTERL association, a wide ranging disorder encompassing various deformities including those of the spine, the kidneys, the anus and the esophagus (gullet).

Beyond gene and protein defects, the overexpression of the Shh gene can result in equally severe consequences. With the Hedgehog pathway being a key driver of cell proliferation (i.e. cell growth) in some tissues, too much of the ShhN protein has been linked to tumour propagation, which leads to cancer. In particular, skin cancer and medulloblastoma, the most common brain tumour in children, has been linked to ShhN protein overexpression.

Polydactyly (additional fingers or toes) has also been linked to incorrect levels of ShhN protein expression as higher levels of ShhN protein expression is linked to limb formation.

Conclusion

It is remarkable that a protein named after a video game character would play such a significant role in human development. The discovery of the Sonic Hedgehog protein highlights the balance scientists try to achieve between serious research and a bit of light-hearted fun to intrigue the general public. In today’s increasingly volatile world with scientific scepticism on the rise, the “fun” side of science becomes all the more important to cultivate a sense of relatability with the audience it is meant to benefit — the general public. While we may gawk at the name and its origin, we must ultimately appreciate that the scientists behind it were driven by the quest for scientific knowledge and made a significant contribution to our understanding of how we develop.

References:

Image Credit:

https://proteininnovation.org/2024/04/adrian-salic-sonic-hedgehog-qa/

Issue 8 - August 2025

PB Fact Files #2: Sonic hedgehog protein