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{{for|the video game character and its namesake|Sonic the Hedgehog (character)}}
{{missing information|limb digit development, [[polydactyly]]|date=June 2016}}
{{Infobox_gene}}

'''Sonic hedgehog''' is a protein that in humans is encoded by the ''SHH'' [[gene]].<ref name="pmid7590746">{{cite journal | vauthors = Marigo V, Roberts DJ, Lee SM, Tsukurov O, Levi T, Gastier JM, Epstein DJ, Gilbert DJ, Copeland NG, Seidman CE | title = Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog | journal = Genomics | volume = 28 | issue = 1 | pages = 44–51 | date = July 1995 | pmid = 7590746 | doi = 10.1006/geno.1995.1104}}</ref> It is the best studied [[Ligand (biochemistry)|ligand]] of the [[hedgehog signaling pathway]], others being [[DHH (hedgehog)|desert hedgehog]] (DHH) and [[Indian Hedgehog (protein)|Indian hedgehog]] (IHH). It plays a key role in the [[embryogenesis|development]] of animals, from insects to mammals. In [[vertebrate]]s, it is involved in [[organogenesis]], including the growth of [[digit (anatomy)|digits]] on limbs and the organization of the brain. Sonic hedgehog is an archetypal example of a [[morphogen]] as defined by [[Lewis Wolpert]]'s [[French flag model]]—a molecule that [[diffusion|diffuses]] to form a [[concentration gradient]] and has different effects on the cells of the developing [[embryo]] depending on its concentration. Sonic hedgehog is also active in adults; for example, it controls the [[cell division|proliferation]] of [[adult stem cell]]s and has been implicated in the [[carcinogenesis|development of some cancers]].

{{anchor|Discovery}}

== Discovery and name ==
The hedgehog gene (''[[Hedgehog (cell signaling)|hh]]'') was first identified in the fruit-fly ''[[Drosophila melanogaster]]'' in the classic Heidelberg screens of [[Christiane Nüsslein-Volhard]] and [[Eric Wieschaus]], as published in 1980.<ref name="pmid6776413">{{cite journal | vauthors = Nüsslein-Volhard C, Wieschaus E | title = Mutations affecting segment number and polarity in Drosophila | journal = Nature | volume = 287 | issue = 5785 | pages = 795–801 | date = October 1980 | pmid = 6776413 | doi = 10.1038/287795a0}}</ref> These [[Genetic screen|screens]], which led to them winning the [[Nobel Prize in Physiology or Medicine|Nobel Prize]] in 1995 along with developmental geneticist [[Edward B. Lewis]], identified genes that control the [[segmentation (biology)|segmentation]] pattern of the ''[[Drosophila]]'' embryos. The ''hh'' loss of function [[mutant]] [[phenotype]] causes the embryos to be covered with denticles, small pointy projections resembling the spikes of a [[hedgehog]]. Investigations aimed at finding a ''hedgehog'' equivalent in vertebrates by [[Philip Ingham]], Andrew P. McMahon, and [[Clifford Tabin]], revealed three [[Homology (biology)|homologous genes]].<ref name="pmid8269519">{{cite journal | vauthors = Krauss S, Concordet JP, Ingham PW | title = A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos | journal = Cell | volume = 75 | issue = 7 | pages = 1431–44 | date = December 1993 | pmid = 8269519 | doi = 10.1016/0092-8674(93)90628-4}}</ref><ref name="pmid7916661">{{cite journal | vauthors = Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP | title = Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity | journal = Cell | volume = 75 | issue = 7 | pages = 1417–30 | date = December 1993 | pmid = 7916661 | doi = 10.1016/0092-8674(93)90627-3 }}</ref><ref name="pmid8269518">{{cite journal | vauthors = Riddle RD, Johnson RL, Laufer E, Tabin C | title = Sonic hedgehog mediates the polarizing activity of the ZPA | journal = Cell | volume = 75 | issue = 7 | pages = 1401–16 | year = 1993 | pmid = 8269518 | doi = 10.1016/0092-8674(93)90626-2 }}</ref><ref name="url_NYT">{{cite web | url = https://www.nytimes.com/1994/01/11/science/biologists-find-key-genes-that-shape-patterning-of-embryos.html?pagewanted=all&src=pm | title = Biologists Find Key Genes That Shape Patterning of Embryos | author = Angier N | date = 1994-01-11 | work = Science | publisher = New York Times }}</ref>

Two of these, ''desert hedgehog'' and ''Indian hedgehog'', were named for species of hedgehogs, while ''sonic hedgehog'' was named after [[Sonic the Hedgehog (character)|Sonic the Hedgehog]], the protagonist character of the [[Sonic the Hedgehog|eponymous video game franchise]].<ref>{{cite book|author = Anwood R | authorlink = Robert Anwood | title = Emus Can't Walk Backwards | publisher = Ebury Press | date = 2007-09-06 | pages = 113–114 | isbn = 978-0-09-192151-4 |url= https://books.google.com/books?id=00U4ECEqJ0kC&q=sonic }}</ref><ref>{{cite news |url= http://www.nature.com/nature/journal/v438/n7070/full/438897a.html |publisher= Nature |volume= 438 |issue= 897 |date= 2005-12-15 | doi= 10.1038/438897a |title= Pokémon blocks gene name |author= Tom Simonite |accessdate= 2013-05-23 }}</ref> The gene was named as such by Robert Riddle, who was a postdoctoral fellow at the [[Clifford Tabin|Tabin Lab]], after he saw a Sonic comic book his daughter owned.<ref name="nyt1994">{{cite news | url=https://www.nytimes.com/1994/01/11/science/a-gene-named-sonic.html | title = A Gene Named Sonic | date = 1994-01-11 | journal = The New York Times }}</ref><ref>{{cite web | title = Cliff Tabin: Super Sonic An Interview | url = http://web.med.harvard.edu/sites/murmur/html/articles/041204/041204_akeen.asp | date = April 12, 2004 | first1 = Annalise | last1 = Keen | first2 = Cliff | last2 = Tabin | name-list-format = vanc | publisher = The Weekly Murmur }}</ref> In the [[Zebra Danio|zebrafish]], two of the three vertebrate ''hh'' genes are duplicated: ''SHH a'',<ref name="url_zfin.org_SHH a">{{cite web | url = http://zfin.org/cgi-bin/webdriver?MIval=aa-markerview.apg&OID=ZDB-GENE-980526-166 | title = Zebrafish SHHa | website = | publisher = University of Oregon | pages = | archiveurl = | archivedate = | accessdate = }}</ref> ''SHH b''<ref name="url_zfin.org_SHH b">{{cite web | url = http://zfin.org/cgi-bin/webdriver?MIval=aa-markerview.apg&OID=ZDB-GENE-980526-41 | title = Zebrafish SHHb | website = | publisher = University of Oregon | pages = | archiveurl = | archivedate = | accessdate = }}</ref> (formerly described as ''tiggywinkle hedgehog'', named for [[The Tale of Mrs. Tiggy-Winkle|Mrs. Tiggy-Winkle]], a character from [[Beatrix Potter]]'s books for children), ''ihha'' and ''ihhb''<ref name="Currie">{{cite journal | vauthors = Currie PD, Ingham PW | title = Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish | journal = Nature | volume = 382 | issue = 6590 | pages = 452–5 | date = August 1996 | pmid = 8684485 | doi = 10.1038/382452a0 }}</ref> (formerly described as ''echidna hedgehog'', named for the [[Echidna|spiny anteater]] and not for the character [[Knuckles the Echidna]] in the ''Sonic'' franchise).

== Function ==
Of the ''hh'' homologues, ''SHH'' has been found to have the most critical roles in development, acting as a [[morphogen]] involved in patterning many systems, including the [[anterior pituitary]],<ref name="Herzog">{{cite journal | vauthors = Herzog W, Zeng X, Lele Z, Sonntag C, Ting JW, Chang CY, Hammerschmidt M | title = Adenohypophysis formation in the zebrafish and its dependence on sonic hedgehog | journal = Dev. Biol. | volume = 254 | issue = 1 | pages = 36–49 | date = February 2003 | pmid = 12606280 | doi = 10.1016/S0012-1606(02)00124-0 }}</ref> [[pallium (neuroanatomy)|pallium]] of the brain,<ref>{{cite journal | vauthors = Rash BG, Grove EA | title = Patterning the dorsal telencephalon: a role for sonic hedgehog? | journal = The Journal of Neuroscience | volume = 27 | issue = 43 | pages = 11595–603 | date = Oct 2007 | pmid = 17959802 | pmc = 6673221 | doi = 10.1523/JNEUROSCI.3204-07.2007 }}</ref> [[spinal cord]],<ref name="Lewis">{{cite journal | vauthors = Lewis KE, Eisen JS | title = Hedgehog signaling is required for primary motoneuron induction in zebrafish | journal = Development | volume = 128 | issue = 18 | pages = 3485–95 | date = September 2001 | pmid = 11566854 | doi = }}</ref> [[lung]]s,<ref name="Wolpert 5">{{cite book|last1=Wolpert|first1=Lewis|title=Principles of Development|date=2015|publisher=Oxford University Press|pages=500|edition=5th}}</ref> teeth,<ref name="Dassule">{{cite journal | vauthors = Dassule HR, Lewis P, Bei M, Maas R, McMahon AP | title = Sonic hedgehog regulates growth and morphogenesis of the tooth | journal = Development | volume = 127 | issue = 22 | pages = 4775–85 | date = November 2000 | pmid = 11044393 | doi = | url = http://dev.biologists.org/cgi/reprint/127/22/4775.pdf }}</ref> and the [[thalamus]] by the ''[[zona limitans intrathalamica]]''.<ref name="Scholpp">{{cite journal | vauthors = Scholpp S, Wolf O, Brand M, Lumsden A | title = Hedgehog signalling from the ''zona limitans intrathalamica'' orchestrates patterning of the zebrafish diencephalon | journal = Development | volume = 133 | issue = 5 | pages = 855–64 | date = March 2006 | pmid = 16452095 | doi = 10.1242/dev.02248 }}</ref><ref>{{cite journal | vauthors = Rash BG, Grove EA | title = Shh and Gli3 regulate formation of the telencephalic-diencephalic junction and suppress an isthmus-like signaling source in the forebrain | journal = Developmental Biology | volume = 359 | issue = 2 | pages = 242–50 | date = Nov 2011 | pmid = 21925158 | doi = 10.1016/j.ydbio.2011.08.026 | pmc=3213684}}</ref> In vertebrates, the [[limb development|development]] of [[limb (anatomy)|limbs]] and [[digit (anatomy)|digits]] depends on the secretion of sonic hedgehog by the [[zone of polarizing activity]], located on the posterior side of the embryonic [[limb bud]].<ref name="pmid8269518"/> Mutations in the human sonic hedgehog gene, ''SHH'', cause [[holoprosencephaly]] type 3 HPE3 as a result of the loss of the [[ventral]] midline. The sonic hedgehog transcription pathway has also been linked to the formation of specific kinds of cancerous tumors, including the embryonic [[cerebellum|cerebellar]] tumor,<ref name="ReferenceA">{{cite journal | vauthors = Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM | title = Molecular subgroups of medulloblastoma: the current consensus | journal = Acta Neuropathologica | volume = 123 | issue = 4 | pages = 465–72 | date = April 2012 | pmid = 22134537 | pmc = 3306779 | doi = 10.1007/s00401-011-0922-z }}</ref> and [[medulloblastoma]],<ref>{{cite journal | vauthors = DeSouza RM, Jones BR, Lowis SP, Kurian KM | title = Pediatric medulloblastoma - update on molecular classification driving targeted therapies | journal = Frontiers in Oncology | volume = 4 | pages = 176 | date = 22 July 2014 | pmid = 25101241 | doi = 10.3389/fonc.2014.00176 | pmc=4105823}}</ref> as well as the progression of [[prostate cancer]] tumours.<ref>{{cite journal|title=Paracrine Sonic Hedgehog Signaling Contributes Significantly to Acquired Steroidogenesis in the Prostate Tumor Microenvironment|journal=International Journal of Cancer|volume=140|issue=2|pages=358–369|date=2016|pmid=27672740|doi=10.1002/ijc.30450|vauthors=Lubik AA, Nouri M, Truong S, Ghaffari M, Adomat HH, Corey E, Cox ME, Li N, Guns ES, Yenki P, Pham S, Buttyan R}}</ref> For SHH to be expressed in the developing embryo limbs, a morphogen called [[fibroblast growth factor]]s must be secreted from the [[apical ectodermal ridge]].<ref>{{cite journal | vauthors = Tabin C, Riddle R | title = How Limbs Develop|journal=Scientific American | date = February 1999 | volume = 280| issue = 2| pages = 74–9 | doi = 10.1038/scientificamerican0299-74| pmid = 9924814}}</ref>

Sonic hedgehog has also been shown to act as an [[Axon guidance|axonal guidance cue]]. It has been demonstrated that SHH attracts [[commissural]] [[axons]] at the ventral midline of the developing spinal cord.<ref name="Charron_2003">{{cite journal | vauthors = Charron F, Stein E, Jeong J, McMahon AP, Tessier-Lavigne M | title = The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance | journal = Cell | volume = 113 | issue = 1 | pages = 11–23 | year = 2003 | pmid = 12679031 | doi = 10.1016/S0092-8674(03)00199-5 }}</ref> Specifically, SHH attracts [[retinal ganglion cell]] (RGC) axons at low concentrations and repels them at higher concentrations.<ref name="Kolpak">{{cite journal | vauthors = Kolpak A, Zhang J, Bao ZZ | title = Sonic hedgehog has a dual effect on the growth of retinal ganglion axons depending on its concentration | journal = J. Neurosci. | volume = 25 | issue = 13 | pages = 3432–41 | date = March 2005 | pmid = 15800198 | pmc = 1564194 | doi = 10.1523/JNEUROSCI.4938-04.2005 }}</ref> The absence (non-expression) of SHH has been shown to control the growth of nascent hind limbs in [[cetacean]]s<ref name="Thewissen">{{cite journal | vauthors = [[JGM "Hans" Thewissen|Thewissen J]], Cohn MJ, Stevens LS, Bajpai S, Heyning J, Horton WE | title = Developmental basis for hind-limb loss in dolphins and origin of the cetacean bodyplan | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 22 | pages = 8414–8 | date = May 2006 | pmid = 16717186 | pmc = 1482506 | doi = 10.1073/pnas.0602920103 }}</ref> ([[whale]]s and [[dolphin]]s).

=== Patterning of the central nervous system ===
The sonic hedgehog (SHH) signaling molecule assumes various roles in patterning the [[central nervous system]] (CNS) during [[vertebrate]] [[developmental biology|development]]. One of the most characterized functions of SHH is its role in the induction of the [[floor plate]] and diverse ventral cell types within the [[neural tube]].<ref name="pmid11002335">{{cite journal | vauthors = Litingtung Y, Chiang C | title = Control of SHH activity and signaling in the neural tube | journal = Developmental Dynamics | volume = 219 | issue = 2 | pages = 143–54 | date = October 2000 | pmid = 11002335 | doi = 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1050>3.0.CO;2-Q }}</ref> The [[notochord]], a structure derived from the axial [[mesoderm]], produces SHH, which travels extracellularly to the ventral region of the neural tube and instructs those cells to form the floor plate.<ref name="pmid7580143">{{cite journal | vauthors = Placzek M | title = The role of the notochord and floor plate in inductive interactions | journal = Current Opinion in Genetics & Development | volume = 5 | issue = 4 | pages = 499–506 | date = August 1995 | pmid = 7580143 | doi = 10.1016/0959-437X(95)90055-L }}</ref> Another view for floor plate induction hypothesizes that some precursor cells located in the notochord are inserted into the neural plate before its formation, later giving rise to the floor plate.<ref name="pmid9751734">{{cite journal | vauthors = Teillet MA, Lapointe F, Le Douarin NM | title = The relationships between notochord and floor plate in vertebrate development revisited. | journal = Proceedings of the National Academy of Sciences USA | volume = 95 | issue = 20 | pages = 11733–8 | date = September 1998 | pmid = 9751734 | pmc = 21709 | doi = 10.1073/pnas.95.20.11733 }}</ref>

The [[neural tube]] itself is the initial groundwork of the [[Central nervous system|vertebrate CNS]], and the [[floor plate]] is a specialized structure and is located at the ventral midpoint of the neural tube. Evidence supporting the notochord as the signaling center comes from studies in which a second notochord is implanted near a neural tube in vivo, leading to the formation of an ectopic floor plate within the neural tube.<ref name="pmid3834777">{{cite journal | vauthors = van Straaten HW, Hekking JW, Thors F, Wiertz-Hoessels EL, Drukker J | title = Induction of an additional floor plate in the neural tube | journal = Acta Morphol Neerl Scand | volume = 23 | issue = 2 | pages = 91–7 | date = October 1985 | pmid = 3834777 | doi = }}</ref>

{{Gallery
| title =
| width = 250
| height = 250
| lines = 2
| File:Shh Gradient In Neural Tube.svg|alt1 = morphogens that pattern the dorsoventral axes of the neural tube | SHH and BMP gradients in the vertebrate neural tube
| File:Ectopic Floor Plate.svg|alt2=Depiction of the formation of an ectopic floor plate within the neural tube in the presence of a second notochord | Ectopic floor plate formation
| File:Neural Tube Progenitor Domains.svg|alt3=Depiction of domains of the ventral neuronal cell types in the neural tube | Ventral neural domains in neural tube
}}

Sonic hedgehog is the [[secreted protein]] which mediates signaling activities of the notochord and floor plate.<ref>{{cite journal|vauthors=Patten I, Placzek M|lastauthoramp=yes | volume = 57|issue=12 | pages = 1695–1708 | year = 2000 | doi = 10.1007/PL00000652|pmid=11130176 | url = |title=The role of Sonic hedgehog in neural tube patterning |journal=Cellular and Molecular Life Sciences }}</ref> Studies involving [[ectopic expression]] of SHH ''in vitro''<ref name="pmid7753196 ">{{cite journal | vauthors = Martí E, Bumcrot DA, Takada R, McMahon AP | title = Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. | journal = Nature | volume = 375 | issue = 6529 | pages = 322–325 | date = May 1995 | pmid = 7753196 | doi = 10.1038/375322a0 }}</ref> and ''in vivo''<ref name="pmid8929535">{{cite journal | vauthors = Ericson J, Morton S, Kawakami A, Roelink H, Jessell TM | title = Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity | journal = Cell | volume = 87 | issue = 4 | pages = 661–73 | date = November 1996 | pmid = 8929535 | doi = 10.1016/S0092-8674(00)81386-0 }}</ref> result in floor plate induction, and [[Differentiation (cellular)|differentiation]] of [[motor neuron]] and ventral [[interneurons]]. On the other hand, mice mutant for SHH lack ventral spinal cord characteristics.<ref name="pmid8837770">{{cite journal | vauthors = Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA | title = Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function | journal = Nature | volume = 383 | issue = 6599 | pages = 407–13 | date = October 1996 | pmid = 8837770 | doi = 10.1038/383407a0 }}</ref>''In vitro'' blocking of SHH signaling using [[antibody|antibodies]] against it shows similar phenotypes.<ref name="pmid8929535"/> SHH exerts its effects in a concentration-dependent manner,<ref name="pmid2237443">{{cite journal | vauthors = Placzek M, Tessier-Lavigne M, Yamada T, Jessell T, Dodd J | title = Mesodermal control of neural cell identity: floor plate induction by the notochord | journal = Science | volume = 250 | issue = 4983 | pages = 985–8 | date = November 1990 | pmid = 2237443 | doi = 10.1126/science.2237443 }}</ref> so that a high concentration of SHH results in a local [[Enzyme inhibition|inhibition]] of [[Cell proliferation|cellular proliferation]].<ref name="pmid15936325">{{cite journal | vauthors = Wilson L, Maden M | title = The mechanisms of dorsoventral patterning in the vertebrate neural tube | journal = Dev. Biol. | volume = 282 | issue = 1 | pages = 1–13 | date = June 2005 | pmid = 15936325 | doi = 10.1016/j.ydbio.2005.02.027 }}</ref> This inhibition causes the floor plate to become thin compared to the lateral regions of the [[neural tube]]. Lower concentration of SHH results in cellular proliferation and induction of various ventral neural cell types.<ref name="pmid8929535"/> Once the [[floor plate]] is established, cells residing in this region will subsequently express SHH themselves<ref name="pmid15936325" /> generating a [[concentration gradient]] within the neural tube.

Although there is no direct evidence of a SHH [[Concentration gradient|gradient]], there is indirect evidence via the visualization of [[Patched|Patched (''Ptc'')]] gene expression, which encodes for the [[ligand]] binding domain of the [[SHH receptor]]<ref name="pmid8906787 ">{{cite journal | vauthors = Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillips H, Noll M, Hooper JE, de Sauvage F, Rosenthal A | title = The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog | journal = Nature | volume = 384 | issue = 6605 | pages = 129–34 | date = November 1996 | pmid = 8906787 | doi = 10.1038/384129a0 }}</ref> throughout the ventral neural tube.<ref name="pmid8790332">{{cite journal | vauthors = Marigo V, Tabin CJ | title = Regulation of patched by sonic hedgehog in the developing neural tube | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 18 | pages = 9346–51 | year = 1996 | pmid = 8790332 | pmc = 38430 | doi = 10.1073/pnas.93.18.9346 }}</ref> ''In vitro'' studies show that incremental two- and threefold changes in SHH concentration give rise to motor neuron and different interneuronal subtypes as found in the ventral spinal cord.<ref name="pmid9598380">{{cite journal | vauthors = Ericson J, Briscoe J, Rashbass P, van Heyningen V, Jessell TM | title = Graded sonic hedgehog signaling and the specification of cell fate in the ventral neural tube | journal = Cold Spring Harb Symp Quant Biol | volume = 62 | pages = 451–66 | year = 1997 | pmid = 9598380 | doi = 10.1101/SQB.1997.062.01.053 }}</ref> These incremental changes ''in vitro'' correspond to the distance of [[Protein domain|domains]] from the signaling tissue (notochord and floor plate) which subsequently differentiates into different neuronal subtypes as it occurs ''in vitro''.<ref name="pmid9230312">{{cite journal | vauthors = Ericson J, Rashbass P, Schedl A, Brenner-Morton S, Kawakami A, van Heyningen V, Jessell TM, Briscoe J | title = Pax6 controls progenitor cell identity and neuronal fate in response to graded SHH signaling. | journal = Cell | volume = 90 | issue = 1 | pages = 169–80 | date = July 1997 | pmid = 9230312 | doi = 10.1016/S0092-8674(00)80323-2 }}</ref> Graded SHH signaling is suggested to be mediated through the [[GLI1|Gli]] family of proteins which are vertebrate homologues of the ''Drosophila'' [[zinc-finger]]-containing [[transcription factor]] ''[[Cubitus interruptus]]'' (''Ci'') . ''Ci'' is a crucial mediator of hedgehog (''Hh'') signaling in ''Drosophila''.<ref name="pmid15205520">{{cite journal | vauthors = Lum L, Beachy PA | title = The Hedgehog response network: sensors, switches, and routers. | journal = Science | volume = 304 | issue = 5678 | pages = 1755–9 | date = June 2004 | pmid = 15205520 | doi = 10.1126/science.1098020 | citeseerx = 10.1.1.476.3902 }}</ref> In vertebrates three different Gli proteins are present, viz. [[Gli1]], [[Gli2]] and [[Gli3]], which are expressed in the neural tube.<ref name="pmid9584120">{{cite journal | vauthors = Ruiz i Altaba A | title = Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog | journal = Development | volume = 125 | issue = 12 | pages = 2203–12 | date = June 1998 | pmid = 9584120 | doi = | url = http://dev.biologists.org/content/125/12/2203.long }}</ref> Mice mutant for Gli1 show normal spinal cord development, suggesting that it is dispensable for mediating SHH activity.<ref name="pmid10725236">{{cite journal | vauthors = Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M, Joyner AL | title = Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. | journal = Development | volume = 127 | issue = 8 | pages = 1593–605 | date = April 2000 | pmid = 10725236 | doi = | url = http://dev.biologists.org/content/127/8/1593.long }}</ref> However Gli2 mutant mice show abnormalities in the ventral spinal cord with severe defects in the floor plate and ventral-most interneurons (V3).<ref name="pmid9655799">{{cite journal | vauthors = Matise MP, Epstein DJ, Park HL, Platt KA, Joyner AL | title = Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. | journal = Development | volume = 125 | issue = 15 | pages = 2759–70 | date = August 1998 | pmid = 9655799 | doi = | url = http://dev.biologists.org/content/125/15/2759.long }}</ref> Gli3 [[Receptor antagonist|antagonizes]] SHH function in a [[Dose (biochemistry)|dose]] dependent manner, promoting dorsal neuronal subtypes. SHH mutant phenotype can be rescued in SHH/Gli3 double [[mutant]].<ref name="pmid11017169">{{cite journal | vauthors = Litingtung Y, Chiang C | title = Specification of ventral neuron types is mediated by an antagonistic interaction between SHH and Gli3. | journal = Nat Neurosci | volume = 3 | issue = 10 | pages = 979–85 | date = October 2000 | pmid = 11017169 | doi = 10.1038/79916 }}</ref> Gli proteins have a C-terminal activation domain and an N-terminal repressive domain.<ref name="pmid9584120"/><ref name="pmid10433919">{{cite journal | vauthors = Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H | title = Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of SHH signaling. | journal = Development | volume = 126 | issue = 17 | pages = 3915–24 | date = September 1999 | pmid = 10433919 | doi = | url = http://dev.biologists.org/content/126/17/3915.long }}</ref>

SHH is suggested to promote the activation function of Gli2 and inhibit repressive activity of Gli3. SHH also seems to promote the activation function of Gli3 but this activity is not strong enough.<ref name="pmid11017169"/> The graded concentration of SHH gives rise to graded activity of Gli 2 and Gli3, which promote ventral and dorsal neuronal subtypes in the ventral spinal cord. Evidence from Gli3 and SHH/Gli3 mutants show that SHH primarily regulates the spatial restriction of [[progenitor cell|progenitor]] domains rather than being inductive, as SHH/Gli3 mutants show intermixing of cell types.<ref name="pmid11017169"/><ref name="pmid12435629">{{cite journal | vauthors = Persson M, Stamataki D, te Welscher P, Andersson E, Böse J, Rüther U, Ericson J, Briscoe J | title = Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. | journal = Genes Dev | volume = 16 | issue = 22 | pages = 2865–78 | date = November 2002 | pmid = 12435629 | pmc = 187477 | doi = 10.1101/gad.243402 }}</ref>

SHH also induces other proteins with which it interacts, and these interactions can influence the sensitivity of a cell towards SHH. Hedgehog-interacting protein ([[HHIP]]) is induced by SHH which in turn attenuates its signaling activity.<ref name="pmid10050855">{{cite journal | vauthors = Chuang PT, McMahon AP | title = Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. | journal = Nature | volume = 397 | issue = 6720 | pages = 617–21 | date = February 1999 | pmid = 10050855 | doi = 10.1038/17611 }}</ref> [[Vitronectin]] is another protein that is induced by SHH; it acts as an obligate co-factor for SHH signaling in the neural tube.<ref name="pmid10603350">{{cite journal | vauthors = Pons S, Martí E | title = Sonic hedgehog synergizes with the extracellular matrix protein vitronectin to induce spinal motor neuron differentiation. | journal = Development | volume = 127 | issue = 2 | pages = 333–42 | date = January 2000 | pmid = 10603350 | doi = | url = http://dev.biologists.org/content/127/2/333.long }}</ref>

There are five distinct progenitor domains in the ventral neural tube, viz. [[Mandibular nerve|V3]] [[interneuron]], motor neurons (MN), [[Maxillary nerve|V2]], [[Ophthalmic nerve|V1]], and V0 interneurons (in ventral to dorsal order).<ref name="pmid9598380"/> These different progenitor domains are established by "communication" between different classes of [[homeobox]] [[transcription factors]]. (See [[Trigeminal nerve]].) These [[transcription factors]] respond to SHH gradient concentration. Depending upon the nature of their interaction with SHH, they are classified into two groups, class I and class II, and are composed of members from the [[Pax genes|Pax]], [[NKX-homeodomain factor|Nkx]], [[DBX1|Dbx]], and [[Iroquois homeobox factor|Irx]] families.<ref name="pmid15936325"/> Class I proteins are repressed at different thresholds of SHH, delineating ventral boundaries of [[Progenitor cell|progenitor domains]]; while class II proteins are activated at different thresholds of SHH, delineating the dorsal limit of domains. Selective cross-[[repressor|repressive]] interactions between class I and class II proteins give rise to five cardinal ventral neuronal subtypes.<ref name="pmid10830170">{{cite journal | vauthors = Briscoe J, Pierani A, Jessell TM, Ericson J | title = A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. | journal = Cell | volume = 101 | issue = 4 | pages = 435–45 | date = May 2000 | pmid = 10830170 | doi = 10.1016/S0092-8674(00)80853-3 }}</ref>

It is important to note that SHH is not the only [[signaling molecule]] exerting an effect on the developing neural tube. Many other molecules, [[Genetic pathway|pathways]], and mechanisms are active (e.g. [[Retinoic acid|RA]], [[Fibroblast growth factor|FGF]], [[Bone morphogenetic proteins|BMP]]), and complex interactions between SHH and other molecules are possible. BMPs are suggested to play a critical role in determining the sensitivity of neural cell to SHH signaling. Evidence supporting this comes from studies using BMP inhibitors which ventralize the fate of the neural plate cell for a given SHH concentration.<ref name="pmid11044400">{{cite journal | vauthors = Liem KF, Jessell TM, Briscoe J | title = Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites. | journal = Development | volume = 127 | issue = 22 | pages = 4855–66 | date = November 2000 | pmid = 11044400 | doi = | url = http://dev.biologists.org/content/127/22/4855.long }}</ref> On the other hand, mutation in BMP antagonists (such as [[noggin (protein)|noggin]]) produces severe defects in ventral-most characteristics of the spinal cord followed by [[ectopic expression]] of BMP in the ventral neural tube.<ref name="pmid9585504 ">{{cite journal | vauthors = McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP | title = Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. | journal = Genes Dev | volume = 12 | issue = 10 | pages = 1438–52 | date = May 1998 | pmid = 9585504 | pmc = 316831 | doi = 10.1101/gad.12.10.1438 }}</ref> Interactions of SHH with Fgf and RA have yet not been studied in molecular detail.

=== Morphogenetic activity ===
The concentration and time-dependent, cell-fate-determining activity of SHH in the [[ventral]] [[neural tube]] makes it a prime example of a [[morphogen]]. In vertebrates, SHH signaling in the ventral portion of the neural tube is most notably responsible for the induction of [[floor plate]] cells and [[motor neurons]].<ref name=" Roelink">{{cite journal | vauthors = Roelink H, Porter JA, Chiang C, Tanabe Y, Chang DT, Beachy PA, Jessell TM | title = Floor Plate and Motor Neuron Induction by Different Concentrations of the Amino-Terminal Cleavage Product of Sonic Hedgehog Autoproteolysis | journal = Cell | volume = 81 | issue = 3 | pages = 445–455 | date = May 1995 | pmid = 7736596 | doi = 10.1016/0092-8674(95)90397-6 }}</ref> SHH emanates from the [[notochord]] and ventral floor plate of the developing neural tube to create a [[concentration gradient]] that spans the dorso-ventral axis and is antagonized by an inverse [[Wnt signaling pathway|Wnt]] gradient which specifies the dorsal spinal chord.<ref name=" Ribes" /><ref>{{cite journal |last1=Muroyama |first1=Y |last2=Fujihara |first2=M |last3=Ikeya |first3=M |last4=Kondoh |first4=H |last5=Takada |first5=S |title=Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord. |journal=Genes & Development |date=1 March 2002 |volume=16 |issue=5 |pages=548–53 |doi=10.1101/gad.937102 |pmid=11877374|pmc=155351 }}</ref> Higher concentrations of the SHH ligand are found in the most ventral aspects of the neural tube and notochord, while lower concentrations are found in the more dorsal regions of the neural tube.<ref name=" Ribes" /> The SHH concentration gradient has been visualized in the neural tube of mice engineered to express a SHH::GFP fusion protein to show this graded distribution of SHH during the time of ventral neural tube patterning.<ref name=" Chamberlain ">{{cite journal | vauthors = Chamberlain CE, Jeong J, Guo C, Allen BL, McMahon AP | title = Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning | journal = Development | volume = 135 | issue = 6 | pages = 1097–1106 | date = March 2008 | pmid = 18272593 | doi = 10.1242/dev.013086 }}</ref>

It is thought that the SHH gradient works to elicit multiple different cell fates by a concentration and time-dependent mechanism that induces a variety of transcription factors in the ventral [[progenitor cells]].<ref name="Ribes">{{cite journal | vauthors = Ribes V, Briscoe J | title = Establishing and interpreting Graded Sonic Hedgehog during Vertebrate Neural Tube Patterning: The Role of Negative Feedback | journal = Cold Spring Harb Perspect Biol | volume = 1| issue = 2 | pages = a002014 | date = August 2009 | pmid = 20066087 | pmc = 2742090 | doi = 10.1101/cshperspect.a002014 }}</ref><ref name=" Chamberlain" /> Each of the ventral progenitor domains expresses a highly individualized combination of transcription factors—Nkx2.2, Olig2, Nkx6.1, Nkx 6.2, Dbx1, Dbx2, Irx3, Pax6, and Pax7—that is regulated by the SHH gradient. These transcription factors are induced sequentially along the SHH concentration gradient with respect to the amount and time of exposure to SHH ligand.<ref name=" Ribes"/> As each population of progenitor cells responds to the different levels of SHH protein, they begin to express a unique combination of transcription factors that leads to neuronal cell fate differentiation. This SHH-induced differential gene expression creates sharp boundaries between the discrete [[Protein domain|domains]] of transcription factor expression, which ultimately patterns the ventral neural tube.<ref name=" Ribes" />

The spatial and temporal aspect of the progressive induction of genes and cell fates in the ventral neural tube is illustrated by the expression domains of two of the most well characterized transcription factors, Olig2 and Nkx2.2.<ref name=" Ribes"/> Early in development the cells at the ventral midline have only been exposed to a low concentration of SHH for a relatively short time, and express the transcription factor Olig2.<ref name=" Ribes"/> The expression of Olig2 rapidly expands in a dorsal direction concomitantly with the continuous dorsal extension of the SHH gradient over time.<ref name=" Ribes"/> However, as the morphogenetic front of SHH ligand moves and begins to grow more concentrated, cells that are exposed to higher levels of the ligand respond by switching off Olig2 and turning on Nkx2.2.,<ref name=" Ribes" /> creating a sharp boundary between the cells expressing the transcription factor Nkx2.2 ventral to the cells expressing Olig2. It is in this way that each of the domains of the six progenitor cell populations are thought to be successively patterned throughout the neural tube by the SHH concentration gradient.<ref name=" Ribes"/> Mutual inhibition between pairs of transcription factors expressed in neighboring domains contributes to the development of sharp boundaries, however, in some cases, inhibitory relationship has been found even between pairs of transcription factors from more distant domains. Particularly, [[NKX2-2]] expressed in the V3 domain is reported to inhibit [[IRX3]] expressed in V2 and more dorsal domains, although V3 and V2 are separated by a further domain termed MN.<ref name="pmid25398016">{{cite journal |vauthors=Lovrics A, Gao Y, Juhász B, Bock I, Byrne HM, Dinnyés A, Kovács KA |title=Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord |journal=PLOS One |volume=9 |issue=11 |pages=11430|date=November 2014 |pmid=25398016 |doi=10.1371/journal.pone.0111430 |pmc=4232242}}</ref>

=== Tooth development ===
Sonic hedgehog (SHH) is a signaling molecule that is encoded by the same gene sonic hedgehog. SHH plays a very important role in organogenesis and most importantly craniofacial development. Being that SHH is a signaling molecule it primarily works by diffusion along a concentration gradient affecting cells in different manners. In early tooth development, SHH is released from the primary [[enamel knot]], a signaling center, to provide positional information in both a lateral and planar signaling pattern in tooth development and regulation of tooth cusp growth.<ref>{{cite book | last1 = Nanci | first1 = Antonio | name-list-format = vanc | title = Ten Cate's Oral Histology: Development, Structure, and Function | date = 2012 | publisher = Elsevier | location = St. Louis, Mo. | isbn = 978-0-323-07846-7 | edition = 8th }}</ref> SHH in particular is needed for growth of epithelial cervical loops, where the outer and inner epitheliums join and form a reservoir for dental stem cells. After the primary enamel knots are apoptosed, the secondary enamel knots are formed. The secondary enamel knots secrete SHH in combination with other signaling molecules to thicken the oral ectoderm and begin patterning the complex shapes of the crown of a tooth during differentiation and mineralization.<ref name="pmid12665545">{{cite journal | vauthors = Thesleff I | title = Epithelial-mesenchymal signalling regulating tooth morphogenesis | journal = J. Cell Sci. | volume = 116 | issue = Pt 9 | pages = 1647–8 | year = 2003 | pmid = 12665545 | doi = 10.1242/jcs.00410 }}</ref> In a knockout gene model, absence of SHH is indicative of [[holoprosencephaly]]. However SHH activates downstream molecules of Gli2 & Gli3. Mutant Gli2 and Gli3 embryos have abnormal development of incisors that are arrested at early in tooth development as well as small molars.<ref name="pmid9655803">{{cite journal | vauthors = Hardcastle Z, Mo R, Hui CC, Sharpe PT | title = The SHH signalling pathway in tooth development: defects in Gli2 and Gli3 mutants | journal = Development | volume = 125 | issue = 15 | pages = 2803–11 | year = 1998 | pmid = 9655803 | doi = }}</ref>

=== Lung development ===
Although SHH is most commonly associated with brain and limb digit development, it is also important in lung development.<ref>{{cite book|last1=Wolpert|first1=Lewis|title=Principles of Development|date=2015|publisher=Oxford University Press|isbn=978-0-19-967814-3|page=500|edition=5th}}</ref><ref name="Bellusci_1997">{{cite journal | vauthors = Bellusci S, Furuta Y, Rush MG, Henderson R, Winnier G, Hogan BL | title = Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis | journal = Development | volume = 124 | issue = 1 | pages = 53–63 | year = 1997 | pmid = 9006067 | doi = | url = http://dev.biologists.org/content/develop/124/1/53.full.pdf }}</ref><ref name="Pepicelli_1998">{{cite journal | vauthors = Pepicelli CV, Lewis PM, McMahon AP | title = Sonic hedgehog regulates branching morphogenesis in the mammalian lung | journal = Current Biology | volume = 8 | issue = 19 | pages = 1083–6 | year = 1998 | pmid = 9768363 | doi = 10.1016/S0960-9822(98)70446-4 }}</ref><ref name="White_2006">{{cite journal | vauthors = White AC, Xu J, Yin Y, Smith C, Schmid G, Ornitz DM | title = FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains | journal = Development | volume = 133 | issue = 8 | pages = 1507–17 | year = 2006 | pmid = 16540513 | doi = 10.1242/dev.02313 }}</ref> Studies using qPCR and knockouts have demonstrated that SHH contributes to embryonic lung development. The mammalian lung branching occurs in the epithelium of the developing [[bronchus|bronchi]] and lungs.<ref>{{cite book|last1=Miura|first1=T|title=Modeling lung branching morphogenesis.|journal=Current Topics in Developmental Biology|date=2008|volume=81|pages=291–310|doi=10.1016/S0070-2153(07)81010-6|pmid=18023732|isbn=9780123742537}}</ref><ref name="Kugler_2015">{{cite journal | vauthors = Kugler MC, Joyner AL, Loomis CA, Munger JS | title = Sonic hedgehog signaling in the lung. From development to disease | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 52 | issue = 1 | pages = 1–13 | year = 2015 | pmid = 25068457 | pmc = 4370254 | doi = 10.1165/rcmb.2014-0132TR | url = }}</ref> SHH expressed throughout the foregut endoderm (innermost of three germ layers) in the distal epithelium where the embryonic lungs are developing.<ref name="Pepicelli_1998" /><ref name="Kugler_2015" /> This suggests that SHH is partially responsible for the branching of the lungs. Further evidence of SHH’s role in lung branching has been seen with qPCR. SHH expression occurs in the developing lungs around embryonic day 11 and is strongly expressed in the buds of the fetal lungs but low in the developing bronchi.<ref name="Pepicelli_1998" /><ref name="Kugler_2015" /> Mice who are deficient in SHH can develop tracheoesophageal fistula (abnormal connection of the esophagus and trachea).<ref name="Cardoso_2006">{{cite journal | vauthors = Cardoso WV, Lü J | title = Regulation of early lung morphogenesis: questions, facts and controversies | journal = Development | volume = 133 | issue = 9 | pages = 1611–24 | year = 2006 | pmid = 16613830 | doi = 10.1242/dev.02310 }}</ref><ref name="Pepicelli_1998" /> Additionally, a double (SHH-/- ) knockout mouse model exhibited poor lung development. The lungs of the SHH double knockout failed to undergo lobation and branching (the abnormal lungs only developed one branch compared to an extensively branched phenotype of the wildtype).<ref name="Pepicelli_1998" />

===Potential regenerative function ===
Sonic hedgehog may play a role in mammalian [[hair cell]] [[regeneration (biology)|regeneration]]. By modulating [[retinoblastoma protein]] activity in rat cochlea, sonic hedgehog allows mature [[hair cell]]s that normally cannot return to a proliferative state to divide and differentiate. [[Retinoblastoma protein]]s suppress cell growth by preventing cells from returning to the [[cell cycle]], thereby preventing proliferation. Inhibiting the activity of Rb seems to allow cells to divide. Therefore, sonic hedgehog, identified as an important regulator of Rb, may also prove to be an important feature in regrowing hair cells after damage.<ref name="Lu_2013">{{cite journal | vauthors = Lu N, Chen Y, Wang Z, Chen G, Lin Q, Chen ZY, Li H | title = Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein | journal = Biochem. Biophys. Res. Commun. | volume = 430 | issue = 2 | pages = 700–5 | year = 2013 | pmid = 23211596 | pmc = 3579567 | doi = 10.1016/j.bbrc.2012.11.088 }}</ref>

== Processing ==
SHH undergoes a series of processing steps before it is secreted from the cell. Newly synthesised SHH weighs 45&nbsp;[[Atomic mass unit|kDa]] and is referred to as the preproprotein. As a secreted protein it contains a short [[signal peptide|signal sequence]] at its N-terminus, which is recognised by the [[signal recognition particle]] during the translocation into the [[endoplasmic reticulum]] (ER), the first step in protein [[secretion]]. Once translocation is complete, the signal sequence is removed by [[signal peptidase]] in the ER. There SHH undergoes autoprocessing to generate a 20&nbsp;kDa N-terminal signaling domain (SHH-N) and a 25&nbsp;kDa C-terminal domain with no known signaling role.<ref name="Bumcrot">{{cite journal | vauthors = Bumcrot DA, Takada R, McMahon AP | title = Proteolytic processing yields two secreted forms of sonic hedgehog | journal = Mol Cell Biol | volume = 15 | issue = 4 | pages = 2294–2303 | date = 1 April 1995 | pmid = 7891723 | pmc = 230457 | doi = 10.1128/MCB.15.4.2294 }}</ref> The cleavage is catalysed by a [[protease]] within the C-terminal domain. During the reaction, a [[cholesterol]] molecule is added to the C-terminus of SHH-N.<ref>{{cite journal|last1=Ingham|title=Mechanisms and functions of Hedgehog signalling across the metazoa|journal=Nature Reviews Genetics |date=2011|volume=12|issue=6|pages=393–406|doi=10.1038/nrg2984|pmid=21502959}}</ref><ref name="Porter">{{cite journal | vauthors = Porter JA, Young KE, Beachy PA | title = Cholesterol modification of hedgehog signaling proteins in animal development | journal = Science | volume = 274 | issue = 5285 | pages = 255–259 | year = 1996 | pmid = 8824192 | doi = 10.1126/science.274.5285.255 }}</ref> Thus the C-terminal domain acts as an [[intein]] and a cholesterol transferase. Another [[hydrophobic]] [[moiety (chemistry)|moiety]], a [[palmitic acid|palmitate]], is added to the alpha-amine of N-terminal [[cysteine]] of SHH-N. This modification is required for efficient signaling, resulting in a 30-fold increase in potency over the non-palmitylated form, and is carried out by a member of the [[MBOAT|membrane-bound O-acyltransferase]] family, [[HHAT|Protein-cysteine N-palmitoyltransferase, HHAT]].<ref name="Pepinsky">{{cite journal | vauthors = Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K, Taylor FR, Wang EA, Galdes A | title = Identification of a palmitic acid-modified form of human Sonic hedgehog | journal = J Biol Chem | volume = 273 | issue = 22 | pages = 14037–14045 | year = 1998 | pmid = 9593755 | doi = 10.1074/jbc.273.22.14037 }}</ref>

== Robotnikinin ==
A potential inhibitor of the Hedgehog signaling pathway has been found and dubbed "Robotnikinin", in honour of Sonic the Hedgehog's nemesis, [[Doctor Eggman|Dr. Ivo "Eggman" Robotnik]].<ref name="pmid19151731">{{cite journal | vauthors = Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, Duffner JL, Taveras KM, Hyman JM, Lee SW, Koehler AN, Chen JK, Fox JL, Mandinova A, Schreiber SL | title = A small molecule that binds Hedgehog and blocks its signaling in human cells | journal = Nat. Chem. Biol. | volume = 5 | issue = 3 | pages = 154–6 | date = March 2009 | pmid = 19151731 | pmc = 2770933 | doi = 10.1038/nchembio.142 }}</ref>

== Controversy surrounding name ==
The gene has been linked to a condition known as [[holoprosencephaly]], which can result in severe brain, skull and facial defects, causing clinicians and scientists to criticize the name on the grounds of it sounding too frivolous. It has been noted that mention of a mutation in a ''sonic hedgehog'' gene might not be well received in a discussion of a serious disorder with a patient or their family.<ref name="nyt1994"/><ref name="pmid16421543">{{cite journal | vauthors = Maclean K | title = Humour of gene names lost in translation to patients | journal = Nature | volume = 439 | issue = 7074 | pages = 266 | date = January 2006 | pmid = 16421543 | doi = 10.1038/439266d | url = }}</ref><ref name="pmid16718675">{{cite journal | vauthors = Cohen MM | title = Problems in the naming of genes | journal = Am. J. Med. Genet. A | volume = 140 | issue = 13 | pages = 1483–4 | date = July 2006 | pmid = 16718675 | doi = 10.1002/ajmg.a.31264 | url = }}</ref>

==Gallery==
{|
| [[File:Shh and Gli proteins interactions.svg|thumb|alt=Interaction between SHH and Gli proteins which gives rise to different ventral neuronal subtypes. | SHH gradient and Gli activity in the vertebrate neural tube.]]
| [[File:Shh processing.svg|thumb|Processing of SHH]]
| [[File:sonichedgehog.svg|thumb]]
|}

== See also ==

* [[Pikachurin]], a retinal protein named after [[Pikachu]]
* [[Zbtb7]], an oncogene which was originally named "[[Pokémon]]"

== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Dorus S, Anderson JR, Vallender EJ, Gilbert SL, Zhang L, Chemnick LG, Ryder OA, Li W, Lahn BT | title = Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates | journal = Human Molecular Genetics | volume = 15 | issue = 13 | pages = 2031–7 | year = 2006 | pmid = 16687440 | doi = 10.1093/hmg/ddl123 }}
* {{cite book |author=Gilbert, Scott F. |title=Developmental biology |publisher=Sinauer Associates |location=Sunderland, Mass |edition=6th |year=2000 |isbn=978-0-87893-243-6 |url-access=registration |url=https://archive.org/details/developmentalbio00gilb }}
* {{cite journal | vauthors = Kim J, Kim P, Hui CC | title = The VACTERL association: lessons from the Sonic hedgehog pathway | journal = Clinical Genetics | volume = 59 | issue = 5 | pages = 306–15 | year = 2001 | pmid = 11359461 | doi = 10.1034/j.1399-0004.2001.590503.x }}
* {{cite journal | vauthors = Morton JP, Lewis BC | title = SHH signaling and pancreatic cancer: implications for therapy? | journal = Cell Cycle | volume = 6 | issue = 13 | pages = 1553–7 | year = 2007 | pmid = 17611415 | doi = 10.4161/cc.6.13.4467 }}
* {{cite journal | vauthors = Mullor JL, Sánchez P, Ruiz i Altaba A | title = Pathways and consequences: Hedgehog signaling in human disease | journal = Trends Cell Biol. | volume = 12 | issue = 12 | pages = 562–9 | year = 2003 | pmid = 12495844 | doi = 10.1016/S0962-8924(02)02405-4 }}
* {{cite journal | vauthors = Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M | title = SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature | journal = American Journal of Medical Genetics | volume = 102 | issue = 1 | pages = 1–10 | year = 2001 | pmid = 11471164 | doi = 10.1002/1096-8628(20010722)102:1<1::AID-AJMG1336>3.0.CO;2-U }}
* {{cite journal | vauthors = Williams JA | title = Hedgehog and spinal cord injury | journal = Expert Opinion on Therapeutic Targets | volume = 9 | issue = 6 | pages = 1137–45 | year = 2006 | pmid = 16300466 | doi = 10.1517/14728222.9.6.1137 }}

{{Refend}}

== External links ==
{{Commons category|Sonic hedgehog}}
* [http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2003/Watson/Sonichedgehog.htm An introductory article on ''SHH''] at [[Davidson College]]
* [http://www.learner.org/channel/courses/biology/units/gendev/experts/incardona.html Rediscovering biology: Unit 7, Genetics of development. Expert interview transcripts, interview with John Incardona, PhD]. explanation of the discovery and naming of the sonic hedgehog gene
* [https://www.nytimes.com/2006/11/12/weekinreview/12schwartz.html ‘Sonic Hedgehog’ sounded funny, at first]. New York Times, November 12, 2006.
* [https://www.ncbi.nlm.nih.gov/books/NBK1378/ GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview]
* [http://ghr.nlm.nih.gov/gene/SHH SHH – sonic hedgehog] US National Library of Medicine
* {{PDBe-KB2|Q15465|Human Sonic hedgehog protein}}
* {{PDBe-KB2|Q62226|Mouse Sonic hedgehog protein}}

{{PDB Gallery|geneid=6469}}
{{Hedgehog signaling pathway}}

{{DEFAULTSORT:Sonic Hedgehog}}
[[Category:Proteins]]
[[Category:Morphogens]]
[[Category:HINT domain]]
[[Category:Cell signaling]]
[[Category:Ligands (biochemistry)]]
[[Category:Genes on human chromosome 7]]
[[Category:Sonic the Hedgehog]]

[[de:Sonic hedgehog]]

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