Pharyngula

Basics: Sonic Hedgehog

Every time I mention this developmentally significant molecule, Sonic hedgehog, I get a volley of questions about whether it is really called that, what it does, and why it keeps cropping up in articles about everything from snake fangs to mouse penises to whale fins to worm brains. The time seems appropriate to give a brief introduction to the hedgehog family of signaling molecules.

First, a brief overview of what Sonic hedgehog, or shh, is, which will also give you an idea about why it keeps coming up in these development papers. We often compare the genome to a toolbox — a collection of tools that play various roles in the construction of an organism. If I had to say what tool Sonic hedgehog is most like (keeping in mind that metaphors should not be overstretched), it would be like a tape measure. It’s going to have multiple uses: as a straightedge, as a paperweight to hold down your blueprints, as something to fence with your coworkers on a break, and even to measure distances. It will be pulled out at multiple times during a construction job, and it’s generically useful — you don’t need one tape measure to measure windows, another to measure doors, and yet another to measure countertops. Sonic hedgehog is just like that, getting whipped out multiple times for multiple uses during development, often being used where structures need to be patterned.

Let’s dig into some of the details. I’m using the 2006 review by Ingham and Placzek for most of this summary, so if you really want to get deeper into the literature, I recommend that paper as a starting point.

How do the molecules work?

Hedgehog molecules are signaling proteins. What that means is that these are small molecules that in this case are secreted into the extracellular environment, where they can diffuse and bind to receptors on nearby cells and trigger changes in gene expression in the target. The specific properties of Hedgehog’s transport and diffusion can be modulated by the attachment of lipid molecules to it, which makes it a rather more flexible kind of signal.

What Hedgehog does is to activate an evolutionarily conserved pathway. Hedgehog binds to a receptor protein embedded in the membrane of cells competent to receive the signal; this receptor is called patched, or PTC for short. PTC then releases an inhibition of a cytoplasmic protein called smoothened (SMO), which then modifies the activity of glioma-associate oncogene homologues (GLI) that enter the nucleus and bind to various genes to switch them on and off. I know. The names don’t help at all. Students just have to memorize them. Here’s a short summary of the Rube Goldberg pathway involved here:

Hedgehog (HH) → Patched (PTC) → Smoothened (SMO) → GLI transcription factors → differential gene activity

For you visual thinkers, here’s a diagram. First, the inactive state, in which no Hedgehog is around:

See? Just like I told you, only more complicated. One difference: This is a diagram of a fly cell, and the fly homolog of GLI is a gene called Cubitus interruptus, or CI, which is modified in two different ways to form CIR and CIA in the diagram.

Below, the state when Hedgehog (HH) is bound to the receptor is illustrated, with the end result being a set of Hedgehog target genes being switched on. Also illustrated here is another set of proteins that facilitate HH binding, with the lovely names of Interference hedgehog (IHOG) and Brother of Interference hedgehog (BOI). Trust me, it gets more complicated the more closely you examine it.

i-dc03a35b5f8c0d5cb413c5c869929341-hh_active.jpg
(Click for larger image)

Hedgehog (HH) proteins signal by binding to the transmembrane proteins Interference hedgehog (IHOG) and Brother of IHOG (BOI), which facilitates the interaction of HH with the multipass transmembrane protein Patched (PTC). This interaction relieves the repressive effect of PTC on the serpentine protein Smoothened (SMO). Like PTC, SMO is an obligate component of the HH pathway, being required for all aspects of HH signal transduction that have so far been described. In Drosophila melanogaster, SMO becomes hyperphosphorylated in response to HH signalling and accumulates in the plasma membrane, whereas in vertebrate cells, the protein localizes to primary cilia following exposure to HH ligands. Once activated, SMO modulates the activities of members of the Glioma-associated oncogene homologue (GLI) transcription-factor family. In D. melanogaster, there is just one GLI-family protein, named Cubitus interruptus (CI), which is crucial for HH signalling. CI is a bifunctional transcription factor with both repressor and activator domains that flank a central DNA-binding zinc-finger domain. In the absence of HH signalling, CI undergoes proteolytic cleavage, which is primed by its phosphorylation by three kinases, Protein kinase A (PKA), Glycogen synthase kinase 3 (GSK3) and Casein kinase 1 (CK1), and mediated by the ubiquitin ligase pathway; this yields a truncated form of the protein that acts exclusively as a repressor of HH target-gene transcription (CIR). Activation of SMO suppresses CI cleavage and promotes the nuclear import of a full-length CI protein (CIA); the resulting depletion of the truncated form of CI relieves the repression of some HH target genes, and the full-length CI protein further enhances their transcription. CI is present in a complex with the COS2 scaffold protein, which recruits PKA, GSK3 and CK1, facilitating phosphorylation of CI on residues that are crucial for its cleavage. COS2 binds directly to the intracellular C-terminal tail of SMO, thereby providing a physical basis for the regulatory interaction between SMO and CI. Exactly how SMO activation abrogates CI processing is unclear, but one clue comes from the dependence of SMO activation on its hyperphosphorylation. Notably, the phosphorylation sites that are essential for SMO activity resemble those that are phosphorylated by PKA, GSK3 and CK1 in CI, leading to the suggestion that the phosphorylated C-terminal tail of SMO might compete with CI for a binding partner that mediates its cleavage. CI also interacts with the Fused (FU) serine threonine kinase that abrogates its sequestration in the cytoplasm by the Suppressor of fused (SU(FU)) protein. A negative-feedback loop is initiated when the BTB/rdx proteins, targets of HH signalling, degrade CI.

Hedgehog as a morphogen

From the diagram above, you might think Hedgehog is limited — it can switch genes on and off. What isn’t shown is that the effect of the protein is dependent on concentration and timing — it isn’t just an on/off switch, it’s an analog switch. As anyone who has done any circuit design knows, this is incredibly useful. Just by increasing the concentration of Hedgehog — turning the dial up — you can get activation of more and more target genes, and stronger expression as well. In addition, cells respond progressively to longer exposures to Hedgehog with greater activation, adding another layer of control.

This is where the comparison to a tape measure is appropriate. Organisms can set up gradients of Hedgehog, and cells along the gradient can measure off where they are, and they switch genes on and off along that gradient in a reliable pattern. What this means is that one signal can be used to generate multiple different outputs, producing the ability to generate patterned distributions of cells. The models below illustrate the multiple ways Hedgehog is able to generate different patterns of gene expression.

i-5472cc76fe4d87a46b12554b17ffa84b-hh_sig.jpg
(Click for larger image)

Signals can specify cell fate in different ways. Blue circles represent the signal-secreting cells; other circles represent the responding cells. In a, the secreting cell establishes a spatially graded distribution of signal across the adjacent field of cells. Each cell adopts a different identity (indicated by different colours) in response to different levels of the signal. This is the classical morphogen paradigm. In b, cell number increases vertically with time. As the secreting cell divides, one of its progeny stops expressing the signal and adopts an identity that is determined by the length of time for which the parental cell has expressed the signal. The integration of signal level over time is represented by the increase in the shading intensity of the secreting cell. Note that the sequence of different cell identities that are generated in this way is the same as in a. In c, only two different identities are specified in response to the signal (arrows): initially, all cells respond to the signal (red circles), but as the cellular field expands through proliferation, some cells move out of range of the signal and adopt a different identity (white circles). In d, the signal acts over a short range to induce two different cell identities; this is accomplished by the movement of one cell away from the source, allowing a second cell that has a different potential or competence to be exposed to the same signal. In e, the competence of cells to respond to the same signal changes over time. In f, cells in different locations respond differently to the same signal.

Patterning the limb

i-28deedb281f6241261708ac0fe4a40cd-hh_bud.jpg
Schematic representation of Wolpert’s spatial morphogen gradient model (4). The hypothetical threshold values postulated to specify the digits are indicated in red. Digits are numbered so that the most anterior digit (the thumb) is 1 and the most posterior one (the little finger or pinky) is 5. The ZPA in the posterior limb bud mesenchyme is indicated in dark blue, and the limb skeletal elements are shown only schematized.

One example of Hedgehog patterning is right in your hand. In early development, the limb begins as a digitless bud, a small protrusion from the body wall that only has polarity. That is, the posterior side of the bud, where the prospective pinky (digit 5) will form, has an area called the Zone of Polarizing Activity (ZPA) that secretes — you guessed it — a Hedgehog protein, specifically a vertebrate form called Sonic hedgehog. And yes, it was named after the Sega video game character. When the gene was discovered, it was identified as a member of the Hedgehog, so it was given an arbitrary name to make its affinity clear. For you Beatrix Potter fans, there is also a Tiggywinkle hedgehog.

The location of the ZPA sets up a gradient of Sonic hedgehog across the limb bud, from very high where the pinky will form, to very low where the thumb will form. Cells across the limb can read that gradient and have different patterns of gene activity turned on, which is what leads to the subsequent development of different digits.

We can also see the different ways Sonic hedgehog regulates the digits. As the diagram below illustrates, the posteriormost digits actually don’t look at concentration — their identity is set by how long they’ve been exposed to shh. The next digits are concentration dependent, and the thumb is the default state — low or no shh specifies the development of the first digit.

i-3aed5b509eeb6805303a31072354840d-hh_limb.jpg
Schematic representation outlining the mechanisms by which Shh contributes to each individual digit in the mouse limb. Digit 1 is not reliant on Shh, at least in the hindlimb. Cells comprising digit 2 never expresses Shh itself, though they are reliant on secretion of Shh from producing cells (paracrine signaling). Approximately half of digit 3 and all of digits 4 and 5 are composed of cells that have expressed Shh (autocrine Shh signaling), and differential identity is thought to be shaped dependent on the length of time cells are exposed to high-level autocrine signaling. Both paracrine and autocrine Shh signaling contributes to digit 3 formation.

Patterning the nervous system

The classic place to find Sonic hedgehog expressed is the central nervous system (CNS) — this was where the importance of the gene product in vertebrate development was first identified. A structure called the floorplate, a band of cells that extends the length of the nervous system on the ventral floor, secretes Sonic hedgehog. Another band of cells, the roofplate, on top of the CNS, secretes another set of signaling molecules, the bone morphogenetic proteins (BMPs) (which have many more roles than simply controlling bone development — it’s too bad they weren’t named after a Nintendo sprite). These two complementary gradients of Shh and BMP generate unique molecular addresses for any cell along the dorsoventral axis, and enable the differentiation of many different cell types. This is a case of two simple inputs generating a multitude of outputs.

i-69756e1c0921415705a32aa877343069-hh_neuro.jpg
(Click for larger image)

Control of Commissural Axon Guid- ance by Patterning Molecules (Left) At early stages, BMPs (purple) from the roof plate (RP) control the generation of distinct neuronal subtypes in the dorsal spinal cord (DL1-DL6), whereas Shh (green) from the floor plate (FP) acts to pattern the ventral spinal cord (V0-V3, MN). (Right) At later stages, commissural axon guidance is influenced sequentially by (1) BMPs (purple) from the RP to direct axons ventrally, (2) combinatorial activities of Netrin-1 and Shh (green) to attract axons to the FP, and (3) Wnt4 (yellow) expression in a caudal-low rostral-high gradient to control rostral turning toward the brain. BMP and Shh signals are shown only on the cross- sectional face of the three-dimensional schematic drawing of the spinal cord but are expressed along the entire rostrocaudal length of the spinal cord. Wnt1 signals (blue) derived from the roof plate act to instruct neural crest (NC) cells to acquire DRG sensory neuron identity. Dorsoventral and rostrocaudal axes are indicated by black arrows.

Other roles

Hedgehog is a morphogen, a molecule that defines cell identity by its concentration, but it is also a mitogen. Mitogens regulate cell activity, so Shh can also signal adjacent cells to proliferate.

Sonic hedgehog downregulation has also been associated with some cancers, especially of the skin and brain. As you might expect, a gene that can regulate cell type and division might be implicated in errors of cell growth and identity…cancers. This gene is not just of concern in embryos, but is important in you right now for maintaining your cellular organization.

The developmental pathways in your immune system are regulated in part by Shh.

Shh is one of the key signaling molecules in generating left-right asymmetries in development. Your heart is skewed to the left and your appendix is on the right because of a pattern modulated by Hedgehog signaling.

In a role that has to be useful in getting funding from aging, balding Republicans, Shh is also important in regulating the organization of smooth muscle and endothelium in a structure that is a complicated maze of spongy tubes and smooth muscle — the penis. Abnormal Shh expression has also been found in men with erectile dysfunction.

Summary

Expect to see Sonic hedgehog and other Hedgehog family members to come up frequently in any discussion of the molecular genetics of animals — they are ubiquitous (except, strangely enough, they are absent in C. elegans) and they have utility in many roles. As I discussed yesterday, they appear in the most surprising roles, as in patterning the distribution of teeth, and seem to be expressed in almost any place where the organism is measuring out and partitioning and organizing a pattern of cell fates.


Arsic D, Beasley SW, Sullivan MJ. (2007) Switched-on Sonic hedgehog: a gene whose activity extends beyond fetal development—to oncogenesis. J Paediatr Child Health 43(6):421-3.

Crompton T, Outram SV, Hager-Theodorides AL (2007) Sonic hedgehog signalling in T-cell development and activation. Nat Rev Immunol 7(9):726-35.

Ingham PW, Placzek M (2006) Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 7(11):841-50.

McGlinn E, Tabin CJ. (2006) Mechanistic insight into how Shh patterns the vertebrate limb. Curr Opin Genet Dev 16(4):426-32.

Podlasek CA, Meroz CL, Korolis H, Tang Y, McKenna KE, McVary KT (2005) Sonic hedgehog, the penis and erectile dysfunction: a review of sonic hedgehog signaling in the penis. Curr Pharm Des 11(31):4011-27.

Salie R, Niederkofler V, Arber S. (2005) Patterning molecules; multitasking in the nervous system. Neuron 45(2):189-92.

Comments

  1. #1 Lips_of_spike
    August 1, 2008

    Nice review, but one minor point: while it’s true that C. elegans doesn’t have Hedgehog, less diverged nematodes do have clear Hedgehog homologues. See Burglin (2008) [http://www.biomedcentral.com/1471-2164/9/127]. C. elegans is just the more famous (and derived) state.

  2. #2 Phoenix Woman
    August 1, 2008

    This is interesting, PZ! Thanks!

    Sonic Hedgehog: Nature’s rheostat.

  3. #3 ThirtyFiveUp
    August 1, 2008

    Thank you.

  4. #4 Hap
    August 1, 2008

    The comments section seems to have changed layout to the standard SciBlogs layout. Is this intentional?

    The explanation is nice.

  5. #5 Phoenix Woman
    August 1, 2008

    So where’s Spiny Norman?

  6. #6 Luke O'Dell
    August 1, 2008

    [i]Fascinating.[/i] I wish I’d gotten into biology instead of physics. At the moment I’m reading a cell biology textbook (Karp) in my spare time, it’s so damn interesting, but heavy going. Can anyone recommend a pop science book on cell biology/genetics?

  7. #7 Jack
    August 1, 2008

    Psalm 1

    Blessed is the man that walketh not in the counsel of the ungodly, nor standeth in the way of sinners, nor sitteth in the seat of the scornful.

    But his delight is in the law of the LORD; and in his law doth he meditate day and night.

    And he shall be like a tree planted by the rivers of water, that bringeth forth his fruit in his season; his leaf also shall not wither; and whatsoever he doeth shall prosper.

    The ungodly are not so: but are like the chaff which the wind driveth away.

    Therefore the ungodly shall not stand in the judgment, nor sinners in the congregation of the righteous.

    For the LORD knoweth the way of the righteous: but the way of the ungodly shall perish.

  8. #8 jb
    August 1, 2008

    Thank you. I’d been wanting to ask about Sonic Hedgehog since you mentioned it the first time, and you just saved me hours of digging through search results.

  9. #9 Makita
    August 1, 2008

    I still like your biology posts best. The only thing that soils it are responses like #7. Yuck!

  10. #10 Pierre
    August 1, 2008

    What’s your problem Jack? What does Psalm 1 have to do with signaling proteins and their interaction with the rest of the cell’s machinerie? Have you even read what PZ wrote?

  11. #11 Luke O'Dell
    August 1, 2008

    …or a book on how to use HTML tags…

  12. #12 ThirtyFiveUp
    August 1, 2008

    Luke O’Dell

    See PZ’s recommendations at:

    http://pharyngula.org/index/weblog/comments/a_book_list_for_evolutionists/

    Accessed from “A Taste of Pharyngula”, complete listing,
    on the left side of the page. Many other good posts are available there.

  13. #13 Wisaakah
    August 1, 2008

    I appreciate the versatility and general awesomeness of hedgehog signaling, but the thought of actually reading a review makes me feel slightly ill. It’s one of those pathways that is involved in so many things that finding a role for it in a new process explains almost nothing. It’s like saying: “I bet mitosis is involved in development”, or “I bet Wnt signaling is involved”.

    Of course, everyone has a favorite and a most hated signaling pathway/process. I’ll just have to leave the hedgehog stuff to better folk than I.

    That being said, thank you, PZ, for writing a review that I could actually read without wanting to stick a fork in my eye. That is no small feat.

  14. #14 Blake Stacey
    August 1, 2008

    Luke O’Dell (#6):

    You could do much worse than starting with Larry Gonick’s Cartoon Guide to Genetics. It has good introductory material on gene regulation (among many other things), which is particularly important for subjects like these.

  15. #15 Tim Drake
    August 1, 2008

    You keep getting asked if its really called that because of the popular video game character.

  16. #16 freelunch
    August 1, 2008

    I think that Sonic and Tiggywinkle were named such, not only because some scientists are whimsical, but because there just aren’t enough real hedgehog forms to match the number of molecule forms in the hh family. “Interference” is bad enough, but “Brother of Interference”? I think scientists need a hh naming convention like that used by the world’s weather services to name cyclonic storms.

  17. #17 Phoenix Woman
    August 1, 2008

    Makita:

    1) Are you using Firefox? If you are, go to 2). If not, get it, then go to 2).

    2) Download and install the Greasemonkey add-on for Firefox.

    3) Download and install killfile.

    4) Next time you see a troll in the comments section of almost any blog, hit the “kill” feature that is now next to said troll’s name. Et la voila — troll vanishes from your sight. Page loads a lot faster, too.

  18. #18 Shaden Freud
    August 1, 2008

    #7

    O Lord, bless this thy morphogen, that with it thou mayest establish cellular positional information, in Thy mercy.

    #5

    DINSDALE!!!

  19. #19 Jared
    August 1, 2008

    Good stuff, but I have a tiny question, what happens when both SHH and BMP are overexpressed? Also, it seems possible to do, but what would happens if the floorplate expresses BMP and the roofplate expresses SHH?

  20. #20 iain
    August 1, 2008

    This is just creepy, I just read about Sonic Hedgehog in “Your inner fish” of Neil Shabin when I came from work today. Talk about coincidence. Although he didn’t say how it worked biologically. Incredible stuff!

  21. #21 Rev. BigDumbChimp
    August 1, 2008

    Thanks for the run down. You knew once you brought it up you’d need to do this. Too many in the video game age group that would perk up at the name.

    interesting and informative

  22. #22 Randy
    August 1, 2008

    Hey, Jack! I can do that, too! Put my fingers in my ears and say, ‘La la la la la la…!’. Maybe if you don’t read it, it won’t exist!

    Pathetic.

  23. #23 Sebastian
    August 1, 2008

    #20:

    God is surely sending you a sign!

  24. #24 ben
    August 1, 2008

    Materialist bias! Goddidit!

  25. #25 Terry Small
    August 1, 2008

    I’m sorry to threadjack. But could we raise the wrath of the Pharyngulites over this proposed bill to define IUDs and the pill as “abortion”?

    http://www.tucsoncitizen.com/daily/local/91560.php

  26. #26 reboho
    August 1, 2008

    Whoa, dude! You’re a biologist too? Guess that whole cracker abuse thing doesn’t pay that well.

    I love it when you get all scientific. It’s amazing to me that so many are so incurious and how much they are missing. I’ll be the first to admit that much of this whizzes by but enough stays so that I will continue to read and enjoy.

  27. #27 Terry Small
    August 1, 2008

    Whoops. I guess you need the Google cache.

    But CNN has a video too.

  28. #28 matthew
    August 1, 2008

    Fascinating article PZ.

    #17

    Thanks Phoenix Woman! Greasemonkey & killfile are very cool.

  29. #29 onclepsycho
    August 1, 2008

    Amazing, thank you.
    For consistency, can you please write a post about “Pikachurin”, now?

  30. #30 David Harper
    August 1, 2008

    Jack (#7) and respondents thereto:

    Proverbs 3:13-16 is much more apposite in this gathering of scientists:

    Happy is he who has found wisdom,
    and the man who has acquired understanding.
    For wisdom is more profitable than silver,
    and the gain she brings is better than gold.
    She is more precious than red coral,
    and all your jewels are no match for her.
    Long life is in her right hand,
    in her left hand are riches and honour.

    I’m not sure where red coral fits in, and the writer was clearly not thinking of academic salaries when he wrote of wisdom bringing riches, but even an atheist like myself can agree with the general sentiment.

  31. #31 Richbank
    August 1, 2008

    The lab I’m working at now actually does work on Shh signaling in Medulloblastomas (Medulloblastomae?), and whenever I try to get a clear overview of the pathway there seems to be sooooo much it does, It’s hard to fully grasp. Thanks for a fairly concise summary!

  32. #32 Katkinkate
    August 1, 2008

    Randy,
    Life’s too short and there is too much good stuff to read to waste time reading troll droppings. No. 7 is not responding to PZ’s article, he’s just a very rude person.

  33. #33 and Jill
    August 1, 2008

    Learned is the man or woman that listeneth not to the counsel of the intolerable, nor standeth in the way of the credulous, nor sitteth in the seat of the pedant.

    But his or her delight is in the laws of NATURE; and in these laws doth he or she cogitate day and night.

    And he or she shall be like fruit fallen from the tree of knowledge, that bringeth forth his or her discoveries in his or her season; his or her inquisitiveness also shall not wither; and whatsoever he or she doeth shall add to the sum of human knowledge.

    The credulous are not so: but are like the chaff which the wind driveth away.

    Therefore the credulous shall not stand in the judgment, nor intolerable in the congregation of the inquisitive.

    For NATURE guideth the way of the inquisitive: but the way of the ignorant shall perish.

  34. #34 NBP
    August 1, 2008

    Very informative PZ! I never cease to be amazed at how complex I am. Oh, and #30, Hear hear!

  35. #35 Makita
    August 1, 2008

    Thank you Phoenix Woman at #17. #7 has done a disappearing act.

  36. #36 Phoenix Woma
    August 1, 2008

    My pleasure, Makita!

  37. #37 Confused
    August 1, 2008

    I’m using the 2006 review by Ingham and Placzek

    Woo, people I know! Phil Ingham was the head of one of the research units at my undergrad university, and Marysia Placzek was one of my lecturers (I almost did a PhD in her lab, and she put my in touch with my current supervisor).

    As a slightly less narcisstic anecdote, while Sonic Hedgehog was named in the Ingham lab, Marysia apparently doesn’t rate it’s namesake, remarking in a lecture that it was named after “some horrible computer game character in the nineties”.

    Personally I think it’s well worth pointing out that the reason hedgehog comes up everywhere is because it’s one of the only signalling molecules that has been well characterised as a morphogen. Others like FGFs, Wnts and BMPs are almost certainly of equal importance and probably perform a comparable plethora of roles in development, they just aren’t as well characterised. It also helps that it’s a relatively small family; there are only a half dozen at most (and that’s in fish, who have extra copies of mostly everything), wheras the others are in the mid teens or more, which makes things that bit more complicated.

  38. #38 Richard Eis
    August 1, 2008

    Sigh…will the next study show that eating earthworms is good for my inner hedgehog… Probably he he.

    Yo Jack, the world has moved on in 2000 years…you gonna have ta run ta keep up honey.

  39. #39 prof weird
    August 1, 2008

    Egads ! Some of those gene names still look familiar !

    My Master’s thesis was : “Cloning and analysis of the cubitus interruptus gene of Drosophila melanogaster”, West Virginia University, 1991.

    Got scooped by two other bigger and better funded labs …

  40. #40 Peter Ashby
    August 1, 2008

    Firstly shh is not entirely universal and it does not do everything. Secondly the details of how it works vary from context to context. Thirdly, reusing molecules like shh in many places both during development and in adults is how you get to make and maintain beasties like us on only 30,000 genes.

    Confused, PZ made it very simple in the limb but the real picture is seriously, wonderously complex with more FGFs than you can shake a stick at and BMPs galore too. Then there are the differential expressions of different Gli genes in the limb. All that is before you understand that the limb is a 4-dimensional structure* and it all changes all the time. It is a complex dance.

    *Embryos are, in a sense not as true at other times, very 4-dimensional creatures. What this means is that changing the timing of something like when a gene gets turned on is often the same as changing where it get turned on.

  41. #41 Ian Andreas Miller
    August 1, 2008

    Is that molecule the fastest thing alive?

  42. #42 bybelknap, FCD
    August 1, 2008

    Jack, this is a local blog for local people. There’s nothing for you here.

  43. #43 jamie
    August 1, 2008

    as a pharmacologist I’m very interested in the fact that a 7TMR appears to be floating around in the cytoplasm! Is SMO really cytoplasmic or not? this review http://dx.doi.org/10.1016/j.bbamem.2006.09.020 didn’t seem to mention it being anywhere apart from the cell membrane.

  44. #44 Nerd of Redhead
    August 1, 2008

    It seems evolution likes to recycle important structures with a few twists. A change in the outer fatty acids and/or saccharides makes shh a new molecule, allowing for differentiation of hand or foot as needed. Ties in very well with gene duplication followed by variation giving rise to new information–not that any creo/IDbot would believe you.
    Don’t be afraid to post some more hard core science. Great job.

  45. #45 Ray C.
    August 1, 2008

    @#7 Jack: Begone, foul troll.

  46. #46 Crudely Wrott
    August 1, 2008

    and Jill @ # 33 gets the award for Best Non-Threatening Parody! Sadly, those so parodied just won’t get it. ‘Course, that makes reading such a delicious comment the more tasty.

  47. #47 Tyler DiPietro
    August 1, 2008

    Right now I’m waiting for someone to identify the “Kunckles echidna” and “Tails fox” genes.

  48. #48 cd
    August 1, 2008

    This blog needs more Drosophilologists. :-)

    The hedgehog gene in D. melanogaster emerged from the famous Wieschaus & Nüsslein-Volhard mutant screen. Best as I recall, in the strong mutant homozygote pre-germband embryo all the non-denticled parasegments are absent and the embryo is a shrumpled half-sized thing consisting almost entirely of denticle bands. Hence “hedgehog”. Then the mammalian people had to come along and screw with that perfectly innocent and descriptive name for their most fun homolog. (Well, it didn’t suffer as much as Fringe did, admittedly, but….)

    Yes, the Smoothened protein is membrane spanning. The diagram is inaccurate.

  49. #49 Tyler DiPietro
    August 1, 2008

    “Right now I’m waiting for someone to identify the “Kunckles echidna” and “Tails fox” genes.”

    Man, trust me to ruin a perfectly nerdy joke by misidentifying the family of biochemical objects I should be analogizing too…

  50. #50 Helioprogenus
    August 1, 2008

    As always, a wonderful explanation of a complex system. Regulatory proteins are never easy to describe, and no matter how comfortable you get with them, there are always new curve balls thrown in the mix. With Shh, we’re probably going to find even more novel pathways and modalities of use. It’s funny that C. Elegans doesn’t possess the gene for regulatory expression. Do they have an analog to Shh in neural cells? One interesting fact I do remember is that they have the same number of genes as us, about 20,000. It’s not the amount of genes that count, but their regulatory sequence that determines an organisms development. Take that you fucking bible-thumping bastards. If we listen to your mindless verbal diarrhea, these impressive processes in nature that link various organisms together and prove without a shadow of a doubt that all organisms on earth have descended from the same ancestor would never have been discovered. You can keep your Adam and Eve, while we focus on recovering our LUCA.

  51. #51 Helioprogenus
    August 1, 2008

    Come to think of it, probably the Hox gene.

  52. #52 AL
    August 1, 2008

    Is that molecule the fastest thing alive?

    That molecule…can really move.
    That molecule…has got attitude.
    That molecule…it’s the fastest thing ali-ee-ive!

  53. #53 LisaJ
    August 1, 2008

    Very nice PZ! Once again, thank you for doing my homework for me.

    We have shown in my lab that Shh intersects with the pRb/E2F tumour suppressor pathway to regulate development of the ventral telencephalon. Also, Shh also has a role in regulating neural stem cell renewal and proliferation – which is what my research concerns (but on the side of regulation by pRb/E2F). Hmmm, this parallel gives me a good idea – I have been trying to think of a topic for my upcoming PhD comprehensive exam, and I think you may have helped me figure it out!

    Thanks again PZ!

  54. #54 Alan Kellogg
    August 1, 2008

    Funny, I thought digits were numbered from the outside in. Palm down in the case of hands. Which makes the pinky the first digit.

  55. #55 Peter Ashby
    August 2, 2008

    No Alan Kellog, in limb research the pinky is always digit 5. Don’t be led astray by that Leonardo figure standing with his palms facing forwards. Think about it when you are on all fours or with your hands on a keyboard. Then you number from inside to outside. The midline is the primary axis and towards the midline is medial, the thumb is medial, the pinky is lateral so you go from medial to lateral when numbering.

    Also I suspect the simplified picture of Smo in the cytoplasm is meant to suggest it is sitting in a vesicle and gets inserted into the membrane or at least it is in a different membrane compartment to Ptc prior to Shh binding.

  56. #56 MarkW
    August 2, 2008

    One for the cdesign proponentsists:

    One of the hallmarks of design is simplicity. This level of (forgive me) insane complexity clearly isn’t designed.

  57. #57 chancelikely
    August 2, 2008

    MarkW #56: I find that ID is much more plausible if you posit that the designer was either Loki or Cthulhu.

  58. #58 Torbjörn larsson, OM
    August 2, 2008

    Thanks, an interesting trip as always.

    it isn’t just an on/off switch, it’s an analog switch. As anyone who has done any circuit design knows, this is incredibly useful.

    Noo … that doesn’t give the correct picture of circuit design IMO, unless you have some specific usage in mind. The common observation is that digital logic is extremely useful as it admits simple and flexible solutions. While analog solutions are complex (so compact) and constrained.

    This explains why digital electronic is ubiquitous. It also explains why a transistor, an analog switch, is so often used in the simpler digital mode. Coincidentally such transistors can be standardized and shrunk considerably as compared to a specific analog use, in some ways making up for that the simple building blocks needs to be manifold to emulate even the simplest analog functions.

    OTOH there will always be advantages to use analog functions in interfaces such as analog interfaces and circuit protection. So if the argument is that an analog switch is an inherently more useful device considered as device design (even if it mostly would be used in digital mode), it is correct.

    @ chancelikely #57:

    And as iml8 reminds us over at PT, IDiots are much more plausible if you posit that they are rabidly yapping pet dogs.

  59. #59 Rickey Miller
    August 2, 2008

    Thanks, my mental acuity has risen once again from your offerings.

  60. #60 Platypus
    August 2, 2008

    I love Drosophila nomenclature. While I can sympathize with the desire to have serious and boring names on everything coming from medical doctors (I know I wouldn’t want to have to tell a parent that their child was dying because of Sonic hedgehog) I think there is just more style in giving it a funny or clever name.

    Since the names of the mutants typically reflect the mutant phenotype, rather than the normal function, the opportunities for fun are tremendous. Found a mutant that increases sensitivity to ethanol? Call it cheapdate.

    (Sadly, when cheapdate was finally cloned it was found to be an allele of a gene that was already named, called amnesiac. Name priority goes to the first published study of the gene, so amnesiac is the correct name and cheapdate is phased out.)

    My favorite mutant was named for a defect caused in the early fly embryo. In the first couple hours of development, the cell cycle is VERY rapid, around 10 minutes from division to division. The nuclei are replicating and dividing synchronously on the surface of the embryo, so fast that they even skip dividing the cytoplasm into individual cells, and just have all the nuclei in a common (syncitial) cytoplasm. Any nuclei that lag behind are aborted rather than given time to catch up; they just fall into the middle of the embryo for later recycling.

    Anyway, a mutant that increased the rate of mitotic errors resulted in a phenotype of a greatly increased rate of these aborted nuclei. So it was given the name: nuclear fallout.

  61. #61 Eliza
    August 3, 2008

    @Platypus – Wasn’t there also a mutant (or maybe it was two) called Ken and Barbie? The resulting flys developed without any genitalia, if I remember correctly.

  62. #62 Karen
    August 3, 2008

    This was a very informative article! I’ve heard a lot about this gene merely because of its name, but I did not know about all the different functions in signaling? I would have liked to hear a discussion of how Shh regulates Hox genes as well since hox genes are so well conserved across animal phyla. I am a prokaryotic biologist working with Shigella, and unfortunately, our genes tend to not have such creative names. It’s still fun to read about research on the darkside (i.e. eukaryotes), though ;)

  63. #63 jomega
    August 3, 2008

    So. I know this guy, and the thing is: his thumbs, like, branch. That is, the end of each thumb splits into two separate fingertips. He’s self-conscious about them, so I’ve been reluctant to ask the fellow about his mutant thumbs. Could such an abnormality be related to the functioning of the protiens under discussion here?

    No, seriously, whaddaya think?

  64. #64 Pat Silver
    August 4, 2008

    Thank you PZ, as usual you have explained a non-trivial concept in a form that I can understand with my fairly basic knowledge of biology.

  65. #65 Karen
    August 4, 2008

    In reference to #63- the disorder you mentioned (i.e. extra extra fingers or fingertips) is called polydactyly. I am not an expert on the subject, but I remember learning in genetics that it can be an autosomal dominant trait if it is isolated and the syndromic condition is autosomal recessive. (All this means is that there are dominant forms of genes and recessive, recessive meaning you need to inherit two copies of it to display a phenotype.) I have not heard any correlation of this condition to the Shh gene, but that does not mean it doesn’t exist- interesting thought. If anyone has read current research on this topic, I would be interested to hear your ideas. In reference to your friend, Jomega, they can be rather easily surgically excised to rebuild a single thumb. Thus, if he is that self-conscious about it, he should just have the surgery. However, if I had that condition, I would be proud of my uniqueness and keep my “mutant thumbs”, but that’s just because I am a deranged biologist ;)

  66. #66 Owlmirror
    August 4, 2008

    There are different types and causes of polydactyly, though.

    Armand Leroi discusses some of them in his book called Mutants.

    It’s been a while since I read the book, but using Amazon search inside, I note the following comes up:

    Polydactyly mutations relax control of sonic hedgehog, altering the balance of power in favour of ubiquity.

    And a citation, which I tracked down to PNAS:

    “Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly”

    http://www.pnas.org/content/99/11/7548

    Of course, it’s all pretty complicated,.

  67. #67 Sili
    August 4, 2008

    See, this is the problem with biology. It’s so damn slow – which means that the bloody biologists have wayyyyyy too much time to sit around coming up with names like these. I’m so glad we have IUPAC in my neck of the woods.

    Thank you for a great summary. Of course people are still gonna ask you in future despite the links to this post. Won’t even help if you bold, underline and capitalise it. We’re habitually lazy buggers.

    Loving the comments, too. 18 and 42 most of all.

  68. #68 Lynnai
    August 17, 2008

    I am pleased that there is a tiggywinkle gene.

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