The name "Sonic hedgehog" may conjure up images of Sega's blue videogame character, tumbling across a screen and collecting gold rings, but its namesake, the human gene Sonic hedgehog, encodes a protein (SHH) whose role in the body is anything but light entertainment. The first hedgehog gene was named for the prickly appearance of the mutant phenotype in Drosophila and thus continuned the whimsical gene naming tradition among fly geneticists. Later, an analogous gene found in mammals was named Sonic hedgehog, a nod to Sega's famous videogame. In humans, defective SHH signaling has been linked to embryonic death, limb defects, heart problems, cancer, and more.
In 2006, scientists discovered that Sonic hedgehog needs a properly constructed cilium, a micro-antenna that projects from almost every cell in the body, in order to do its job. That year, Danwei Huangfu and Kathryn Anderson at the Sloan-Kettering Institute in New York, published that surprising finding in Development. Now, in a follow-up paper published in Cell in November, Anderson and colleagues Sarah Goetz and Karel Liem Jr. described a new gene mutation that causes defects in SHH signaling and a lack of cilia in the neural cells of the embryo1. Goetz named the mouse mutant bartleby, as unmotivated to make cilia as Herman Melville's lazy scribe was to work.
Anderson recalled how her lab first discovered the link between SHH and cilia, "We didn't plan to study cilia; we came across them by accident." The researchers were inducing random genetic mutations in mouse embryos and looking at embryo anatomy when they found defects linked to defects in SHH signaling. When they mapped the mutations, they found that the mutated genes encoded proteins required for ciliogenesis. The new Cell paper follows up on that, Anderson explained.
When Anderson's group mapped the mutated bartleby gene, they found that it encoded the protein Tau tubulin kinase 2 (TTBK2). They showed that TTBK2 is important for removing a protein that blocks cilia construction, CP110. Anderson's group was surprised to discover that the bartebly gene is also mutated in the rare human disease spinocerebellar ataxia type 11 (SCA11). This neurodegenerative disorder leads to poor coordination in walking, hand movement, eye movement, and speech that worsens over time. Anderson's data indicate that the mutations in this rare disease may disrupt ciliogenesis.
"The link to this particular disease was surprising because it is unlike the other disorders that have been linked to cilia so far in a number of ways," Anderson said. In 1990, scientists began to discover the cilia-linked group of diseases known as ciliopathies, and nearly all were recessive genetic diseases that affected a broad range of organs. In contrast, spinocerebellar ataxias are dominant genetic diseases that specifically affect the cerebellum.
Spinocerebellar ataxia is not the only disease with a surprising new link to SHH and cilia. Recent evidence ties cilia defects to the common learning disorder, dyslexia. Several genes are now thought to be critical in dyslexia and now recent work shows that changes in one dyslexia gene, DCDC2, affects SHH signaling and cilia length in cultured neuronal cells2. More recently, a paper published by Gayathri Chandrasekar and colleagues in PLoS One links a different dyslexia gene (DYX1C1) to cilia defects in zebrafish3. DYX1C1 is similar in humans and zebrafish. "We believe that there are good reasons to ask, should we classify dyslexia as a new group of ciliopathies with primarily a cognitive phenotype?" said Juha Kere, principal investigator on the project, at the Karolinska Institute in Sweden.
"It's exciting that cilia may be linked to a new category of human disorders," says Anderson, "but more work needs to be done to determine whether SCA11 results from ciliary dysfunction."
- Goetz SC, Liem KF, Anderson KV (2012) The spinocerebellar ataxia-associated gene tau tubulin kinase 2 controls the initiation of ciliogenesis. Cell. 141: 847-858.This research was supported by NIH Grant NS044385
- Massinen S, Hokkanen ME, Matsson H, Tammimies K, Tapia-Páez I, Dahlström-Heuser V, Kuja-Panula J, Burghoorn J, Jeppsson KE, Swoboda P, Peyrard-Janvid M, Toftgård R, Castrén E, Kere J. (2011) Increased expression of the the dyslexia candidate gene DCDC2 affects length and signaling of primary cilia in neurons. PLoS One. 6(6):e20580
- Chandrasekar G, Vesterlund L, Hultenby K, Tapia-Páez I, Kere J. (2013) The Zebrafish Orthologue of the Dyslexia Candidate Gene DYX1C1 Is Essential for Cilia Growth and Function. PLoS One. 8(5):e63123