View source for Sonic hedgehog protein

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|description= Sonic hedgehog protein is a major signaling molecule of embryonic development in humans and animals, encoded by the SHH gene. This signaling molecule is key
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{{Short description|Critical protein in embryonic development}}
{{Redirect|Sonic hedgehog|the namesake|Sonic the Hedgehog (character)|5=Sonic the Hedgehog (disambiguation)}}
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'''Sonic hedgehog protein''' ('''SHH''') is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene.<ref>{{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>

This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and the organization of the central nervous system, limbs, digits and many other parts of the body. Sonic hedgehog is a morphogen that patterns the developing embryo using a concentration gradient characterized by the French flag model.<ref>{{cite journal | vauthors = Jaeger J, Martinez-Arias A | title = Getting the measure of positional information | journal = PLOS Biology | volume = 7 | issue = 3 | pages = e81 | date = March 2009 | pmid = 19338391 | pmc = 2661971 | doi = 10.1371/journal.pbio.1000081 | doi-access = free }}</ref> This model has a non-uniform distribution of SHH molecules which governs different cell fates according to concentration. Mutations in this gene can cause holoprosencephaly, a failure of splitting in the cerebral hemispheres,<ref>{{cite journal | vauthors = Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, Giannotti A, Imaizumi K, Jones KL, Campo MD, Martin RA, Meinecke P, Pierpont ME, Robin NH, Young ID, Roessler E, Muenke M | title = The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly | journal = Human Molecular Genetics | volume = 8 | issue = 13 | pages = 2479–2488 | date = December 1999 | pmid = 10556296 | doi = 10.1093/hmg/8.13.2479 | doi-access = free }}</ref> as demonstrated in an experiment using SHH knock-out mice in which the forebrain midline failed to develop and instead only a single fused telencephalic vesicle resulted.<ref>{{cite journal | vauthors = Blaess S, Szabó N, Haddad-Tóvolli R, Zhou X, Álvarez-Bolado G | title = Sonic hedgehog signaling in the development of the mouse hypothalamus | journal = Frontiers in Neuroanatomy | volume = 8 | pages = 156 | date = 2015-01-06 | pmid = 25610374 | pmc = 4285088 | doi = 10.3389/fnana.2014.00156 | doi-access = free }}</ref>

Sonic hedgehog still plays a role in differentiation, proliferation, and maintenance of adult tissues. Abnormal activation of SHH signaling in adult tissues has been implicated in various types of cancers including breast, skin, brain, liver, gallbladder and many more.<ref>{{cite journal | vauthors = Jeng KS, Chang CF, Lin SS | title = Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments | journal = International Journal of Molecular Sciences | volume = 21 | issue = 3 | page = 758 | date = January 2020 | pmid = 31979397 | pmc = 7037908 | doi = 10.3390/ijms21030758 | doi-access = free }}</ref>

{{anchor|Discovery}}

== Discovery and naming ==
The hedgehog gene (''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 | s2cid = 4337658 | bibcode = 1980Natur.287..795N }}</ref> These screens, which led to the researchers winning a Nobel Prize in 1995 along with developmental geneticist Edward B. Lewis, identified genes that control the segmentation pattern of the ''Drosophila'' embryos. The ''hh'' loss of function mutant phenotype causes the embryos to be covered with denticles, i.e. 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 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 = 1431–1444 | date = December 1993 | pmid = 8269519 | doi = 10.1016/0092-8674(93)90628-4 | s2cid = 46266627 }}</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 = 1417–1430 | date = December 1993 | pmid = 7916661 | doi = 10.1016/0092-8674(93)90627-3 | s2cid = 6732599 }}</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 = 1401–1416 | date = December 1993 | pmid = 8269518 | doi = 10.1016/0092-8674(93)90626-2 | s2cid = 4973500 }}</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 | vauthors = Angier N | date = 1994-01-11 | work = The New York Times | access-date = 2017-02-18 | archive-date = 2017-08-17 | archive-url = https://web.archive.org/web/20170817082640/http://www.nytimes.com/1994/01/11/science/biologists-find-key-genes-that-shape-patterning-of-embryos.html?pagewanted=all&src=pm | url-status = live }}</ref>

Two of these genes, ''desert hedgehog'' and ''Indian hedgehog'', were named for species of hedgehogs,  while ''sonic hedgehog'' was named after the video game character Sonic the Hedgehog.<ref>{{cite book | vauthors = Anwood R | author-link = 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 | access-date = 2016-10-06 | archive-date = 2017-05-07 | archive-url = https://web.archive.org/web/20170507123129/https://books.google.com/books?id=00U4ECEqJ0kC&q=sonic | url-status = live }}</ref><ref>{{cite journal |journal= Nature |volume= 438 |issue= 897 |date= 2005-12-15 |doi= 10.1038/438897a |title= Pokémon blocks gene name |vauthors= Simonite T |page= 897 |pmid= 16355177 |bibcode= 2005Natur.438..897S |s2cid= 37632823 |doi-access= free }}</ref> The gene was named by Robert Riddle, a postdoctoral fellow at the Tabin Lab, after his wife Betsy Wilder came home with a magazine containing an advert for the first game in the series, ''Sonic the Hedgehog'' (1991).<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 | access-date = 2017-02-18 | archive-date = 2018-02-28 | archive-url = https://web.archive.org/web/20180228013445/http://www.nytimes.com/1994/01/11/science/a-gene-named-sonic.html | url-status = live }}</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 | vauthors = Keen A, Tabin C | publisher = The Weekly Murmur | access-date = April 24, 2014 | archive-url = https://web.archive.org/web/20051110080615/http://web.med.harvard.edu/sites/murmur/html/articles/041204/041204_akeen.asp | archive-date = November 10, 2005 | url-status = dead }}</ref><ref name= ":0">{{cite AV media|  vauthors = Riddle R | title=Ingenious: The Cyclops Gene| publisher= BBC Radio |interviewer= Kat Arney| url= https://www.bbc.co.uk/sounds/play/m000h263| website= BBC.co.uk | date= | access-date= }}</ref> In the 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 | publisher = University of Oregon | archive-url = https://web.archive.org/web/20090625213053/http://zfin.org/cgi-bin/webdriver?MIval=aa-markerview.apg&OID=ZDB-GENE-980526-166| archive-date =2009-06-25| url-status = dead }}</ref> and ''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 | publisher = University of Oregon | archive-url = https://web.archive.org/web/20090626000321/http://zfin.org/cgi-bin/webdriver?MIval=aa-markerview.apg&OID=ZDB-GENE-980526-41| archive-date =2009-06-26| url-status = dead }}</ref> (formerly described as ''tiggywinkle hedgehog'', named for Mrs. Tiggy-Winkle, a character from Beatrix Potter's books for children) and ''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 = 452–455 | date = August 1996 | pmid = 8684485 | doi = 10.1038/382452a0 | s2cid = 4271898 | bibcode = 1996Natur.382..452C }}</ref> (formerly described as ''echidna hedgehog'', named for the 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 = Developmental Biology | volume = 254 | issue = 1 | pages = 36–49 | date = February 2003 | pmid = 12606280 | doi = 10.1016/S0012-1606(02)00124-0 | doi-access = free }}</ref> 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 = 11595–11603 | date = October 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 = 3485–3495 | date = September 2001 | pmid = 11566854 | doi = 10.1242/dev.128.18.3485 }}</ref> lungs,<ref name="Wolpert 5">{{cite book| vauthors = Wolpert L  |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 = 4775–4785 | date = November 2000 | pmid = 11044393 | doi = 10.1242/dev.127.22.4775 }}</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 = 855–864 | date = March 2006 | pmid = 16452095 | doi = 10.1242/dev.02248 | s2cid = 27550686 | doi-access = free }}</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 = 242–250 | date = November 2011 | pmid = 21925158 | pmc = 3213684 | doi = 10.1016/j.ydbio.2011.08.026 }}</ref> In vertebrates, the development of limbs and 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 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 = 465–472 | 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 | pmc = 4105823 | doi = 10.3389/fonc.2014.00176 | doi-access = free }}</ref> as well as the progression of prostate cancer tumors.<ref>{{cite journal | 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 | 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 = January 2017 | pmid = 27672740 | doi = 10.1002/ijc.30450 | s2cid = 2354209 | doi-access = free }}</ref> For SHH to be expressed in the developing embryo limbs, a morphogen called fibroblast growth factors must be secreted from the apical ectodermal ridge.<ref>{{cite journal | vauthors = Riddle RD, Tabin C | title = How limbs develop | journal = Scientific American | volume = 280 | issue = 2 | pages = 74–79 | date = February 1999 | pmid = 9924814 | doi = 10.1038/scientificamerican0299-74 | bibcode = 1999SciAm.280b..74R }}</ref>

Sonic hedgehog has also been shown to act as an 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 | date = April 2003 | pmid = 12679031 | doi = 10.1016/S0092-8674(03)00199-5 | s2cid = 13909497 | doi-access = free }}</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 = The Journal of Neuroscience | volume = 25 | issue = 13 | pages = 3432–3441 | 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 cetaceans<ref name="Thewissen">{{cite journal | vauthors = Thewissen JG, 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 22 | pages = 8414–8418 | date = May 2006 | pmid = 16717186 | pmc = 1482506 | doi = 10.1073/pnas.0602920103 | doi-access = free | bibcode = 2006PNAS..103.8414T }}</ref> (whales and dolphins).

The ''SHH'' gene is a member of the hedgehog gene family with five variations of DNA sequence alterations or splice variants.<ref name="sid: 1">{{cite web |title=ENSG00000164690 |url=https://uswest.ensembl.org/Homo_sapiens/Gene/StructuralVariation_Gene?g=ENSG00000164690;r=7:155799980-155812463 |website=GRCh38 |publisher=Ensembl release 99 |access-date=9 April 2020 |archive-date=1 November 2020 |archive-url=https://web.archive.org/web/20201101152944/https://uswest.ensembl.org/Homo_sapiens/Gene/StructuralVariation_Gene?g=ENSG00000164690;r=7:155799980-155812463 |url-status=live }}</ref> ''SHH'' is located on chromosome seven and initiates the production of sonic hedgehog protein.<ref name="sid: 1" /> This protein sends short- and long-range signals to embryonic tissues to regulate development.<ref name="sid: 2">{{cite web |title=UniprotKB - Q15465 (SHH_HUMAN) |url=https://www.uniprot.org/uniprot/Q15465# |website=UniProt |publisher=UniProt Consortium |access-date=9 April 2020 |archive-date=31 May 2020 |archive-url=https://web.archive.org/web/20200531224811/https://www.uniprot.org/uniprot/Q15465 |url-status=live }}</ref> If the ''SHH'' gene is mutated or absent, the protein sonic hedgehog cannot do its job properly. Sonic hedgehog contributes to cell growth, cell specification and formation, structuring and organization of the body plan.<ref name="sid3">{{cite web |title=SHH gene |url=https://ghr.nlm.nih.gov/gene/SHH#location |website=Genetics Home Reference |publisher=U.S. National Library of Medicine |access-date=9 April 2020 |archive-date=2 April 2020 |archive-url=https://web.archive.org/web/20200402135302/https://ghr.nlm.nih.gov/gene/SHH#location |url-status=live }}</ref> This protein functions as a vital morphogenic signaling molecule and plays an important role in the formation of many different structures in developing embryos.<ref name="sid3" /> The ''SHH'' gene affects several major organ systems, such as the nervous system, cardiovascular system, respiratory system and musculoskeletal system.<ref name="sid: 1" /><ref name="sid: 2" /> Mutations in the ''SHH'' gene can cause malformation of components of these systems, which can result in major problems in the developing embryo. The brain and eyes, for example, can be significantly impacted by mutations in this gene and cause disorders such as Microphthalmia and Holoprosencephaly.<ref name="sid3" /> Microphthalmia is a condition that affects the eyes, which results in small, underdeveloped tissues in one or both eyes.<ref name="sid3" /> This can lead to issues ranging from a coloboma to a single small eye to the absence of eyes altogether.<ref name="sid: 2" /> Holoprosencephaly is a condition most commonly caused by a mutation of the ''SHH'' gene that causes improper separation or turn of the left and right brain<ref name="Lussanet2012">{{cite journal | vauthors = de Lussanet MH, Osse JW | year=2012 | title=An ancestral axial twist explains the contralateral forebain and the optic chiasm in vertebrates | journal=Animal Biology | volume=62 | issue=2 | pages=193–216 | doi=10.1163/157075611X617102 | arxiv=1003.1872 | s2cid=7399128}}</ref> and facial dysmorphia.<ref name="sid: 2" /><ref name="sid3" />  Many systems and structures rely heavily on proper expression of the ''SHH'' gene and subsequent sonic hedgehog protein, earning it the distinction of being an essential gene to development.

=== Patterning of the central nervous system ===
The sonic hedgehog (SHH) signaling molecule assumes various roles in patterning the central nervous system (CNS) during vertebrate 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 = 143–154 | date = October 2000 | pmid = 11002335 | doi = 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1050>3.0.CO;2-Q | s2cid = 221646338 }}</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 of 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 of the United States of America | volume = 95 | issue = 20 | pages = 11733–11738 | date = September 1998 | pmid = 9751734 | pmc = 21709 | doi = 10.1073/pnas.95.20.11733 | doi-access = free | bibcode = 1998PNAS...9511733T }}</ref>

The neural tube itself is the initial groundwork of the vertebrate CNS,  and the floor plate is a specialized structure, 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 Morphologica Neerlando-Scandinavica | volume = 23 | issue = 2 | pages = 91–97 | date = October 1985 | pmid = 3834777 }}</ref>

{{Gallery
| title =
| width = 250
| height = 250
| 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 that mediates signaling activities of the notochord and floor plate.<ref>{{cite journal | vauthors = Patten I, Placzek M | title = The role of Sonic hedgehog in neural tube patterning | journal = Cellular and Molecular Life Sciences | volume = 57 | issue = 12 | pages = 1695–1708 | date = November 2000 | pmid = 11130176 | doi = 10.1007/PL00000652 | s2cid = 20950575 | pmc = 11146859 }}</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 | s2cid = 4362006 | bibcode = 1995Natur.375..322M }}</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 = 661–673 | date = November 1996 | pmid = 8929535 | doi = 10.1016/S0092-8674(00)81386-0 | s2cid = 11578260 | doi-access = free }}</ref> result in floor plate induction and differentiation of motor neuron and ventral interneurons. On the other hand, mice mutants 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 = 407–413 | date = October 1996 | pmid = 8837770 | doi = 10.1038/383407a0 | s2cid = 4339131 | bibcode = 1996Natur.383..407C }}</ref> ''In vitro'' blocking of SHH signaling using 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 = 985–988 | date = November 1990 | pmid = 2237443 | doi = 10.1126/science.2237443 | bibcode = 1990Sci...250..985P }}</ref> so that a high concentration of SHH results in a local inhibition of cellular proliferation.<ref name="pmid15936325">{{cite journal | vauthors = Wilson L, Maden M | title = The mechanisms of dorsoventral patterning in the vertebrate neural tube | journal = Developmental Biology | volume = 282 | issue = 1 | pages = 1–13 | date = June 2005 | pmid = 15936325 | doi = 10.1016/j.ydbio.2005.02.027 | doi-access = free }}</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 gradient, there is indirect evidence via the visualization of 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 = 129–134 | date = November 1996 | pmid = 8906787 | doi = 10.1038/384129a0 | s2cid = 4342540 | bibcode = 1996Natur.384..129S }}</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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 18 | pages = 9346–9351 | date = September 1996 | pmid = 8790332 | pmc = 38430 | doi = 10.1073/pnas.93.18.9346 | doi-access = free | bibcode = 1996PNAS...93.9346M }}</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 Harbor Symposia on Quantitative Biology | volume = 62 | pages = 451–466 | year = 1997 | pmid = 9598380 | doi = 10.1101/SQB.1997.062.01.053 }}</ref> These incremental changes ''in vitro'' correspond to the distance of 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 = 169–180 | date = July 1997 | pmid = 9230312 | doi = 10.1016/S0092-8674(00)80323-2 | s2cid = 17054686 | doi-access = free }}</ref> Graded SHH signaling is suggested to be mediated through the 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 = 1755–1759 | date = June 2004 | pmid = 15205520 | doi = 10.1126/science.1098020 | s2cid = 13949436 | citeseerx = 10.1.1.476.3902 | bibcode = 2004Sci...304.1755L }}</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 = 2203–2212 | date = June 1998 | pmid = 9584120 | doi = 10.1242/dev.125.12.2203 }}</ref> Mice mutants 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 = 1593–1605 | date = April 2000 | pmid = 10725236 | doi = 10.1242/dev.127.8.1593 }}</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 = 2759–2770 | date = August 1998 | pmid = 9655799 | doi = 10.1242/dev.125.15.2759 }}</ref> Gli3 antagonizes SHH function in a dose-dependent manner, promoting dorsal neuronal subtypes. SHH mutant phenotypes can be rescued in a 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 = Nature Neuroscience | volume = 3 | issue = 10 | pages = 979–985 | date = October 2000 | pmid = 11017169 | doi = 10.1038/79916 | s2cid = 10102370 }}</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 = 3915–3924 | date = September 1999 | pmid = 10433919 | doi = 10.1242/dev.126.17.3915 }}</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 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 & Development | volume = 16 | issue = 22 | pages = 2865–2878 | 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 = 617–621 | date = February 1999 | pmid = 10050855 | doi = 10.1038/17611 | s2cid = 204991314 | bibcode = 1999Natur.397..617C }}</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 = 333–342 | date = January 2000 | pmid = 10603350 | doi = 10.1242/dev.127.2.333 }}</ref>

There are five distinct progenitor domains in the ventral neural tube: V3 interneurons,  motor neurons (MN), V2, 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, Nkx, Dbx and Irx families.<ref name="pmid15936325"/> Class I proteins are repressed at different thresholds of SHH delineating ventral boundaries of progenitor domains, while class II proteins are activated at different thresholds of SHH delineating the dorsal limit of domains. Selective cross-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 = 435–445 | date = May 2000 | pmid = 10830170 | doi = 10.1016/S0092-8674(00)80853-3 | s2cid = 17295764 | doi-access = free }}</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, pathways and mechanisms are active (e.g., RA, FGF, 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 that 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 = 4855–4866 | date = November 2000 | pmid = 11044400 | doi = 10.1242/dev.127.22.4855 }}</ref> On the other hand, mutation in BMP antagonists (e.g., noggin) produces severe defects in the 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 & Development | volume = 12 | issue = 10 | pages = 1438–1452 | date = May 1998 | pmid = 9585504 | pmc = 316831 | doi = 10.1101/gad.12.10.1438 }}</ref> Interactions of SHH with Fgf and RA have not yet 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 | s2cid = 18937753 | doi-access = free }}</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 gradient, which specifies the dorsal spinal cord.<ref name=" Ribes" /><ref>{{cite journal | vauthors = Muroyama Y, Fujihara M, Ikeya M, Kondoh H, Takada S | title = Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord | journal = Genes & Development | volume = 16 | issue = 5 | pages = 548–553 | date = March 2002 | pmid = 11877374 | pmc = 155351 | doi = 10.1101/gad.937102 }}</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 | s2cid = 17431502 | doi-access = free }}</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 signaling during vertebrate neural tube patterning: the role of negative feedback | journal = Cold Spring Harbor Perspectives in Biology | 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, Nkx6.2, 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 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 = e111430 | date = November 2014 | pmid = 25398016 | pmc = 4232242 | doi = 10.1371/journal.pone.0111430 | doi-access = free | bibcode = 2014PLoSO...9k1430L }}</ref>

SHH expression in the frontonasal ectodermal zone (FEZ), which is a signaling center that is responsible for the patterned development of the upper jaw, regulates craniofacial development mediating through the miR-199 family in the FEZ. Specifically, SHH-dependent signals from the brain regulate genes of the miR-199 family with downregulations of the miR-199 genes increasing SHH expression and resulting in wider faces, while upregulations of the miR-199 genes decrease SHH expression resulting in narrow faces.<ref>{{cite journal | vauthors = Richbourg HA, Hu DP, Xu Y, Barczak AJ, Marcucio RS | title = miR-199 family contributes to regulation of sonic hedgehog expression during craniofacial development | journal = Developmental Dynamics | volume = 249 | issue = 9 | pages = 1062–1076 | date = September 2020 | pmid = 32391617 | pmc = 7484444 | doi = 10.1002/dvdy.191 }}</ref>

=== Tooth development ===
SHH plays an 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 | vauthors = Nanci A | 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 = Journal of Cell Science | volume = 116 | issue = Pt 9 | pages = 1647–1648 | date = May 2003 | pmid = 12665545 | doi = 10.1242/jcs.00410 | s2cid = 45648812 | doi-access = free }}</ref> In a knockout gene model, absence of SHH is indicative of holoprosencephaly. However, SHH activates downstream molecules of Gli2 and Gli3. Mutant Gli2 and Gli3 embryos have abnormal development of incisors that are arrested in early 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 = 2803–2811 | date = August 1998 | pmid = 9655803 | doi = 10.1242/dev.125.15.2803 }}</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| vauthors = Wolpert L |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 | date = January 1997 | pmid = 9006067 | doi = 10.1242/dev.124.1.53 }}</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 = 1083–1086 | date = September 1998 | pmid = 9768363 | doi = 10.1016/S0960-9822(98)70446-4 | s2cid = 12711144 | doi-access = free | bibcode = 1998CBio....8.1083P }}</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 = 1507–1517 | date = April 2006 | pmid = 16540513 | doi = 10.1242/dev.02313 | s2cid = 23839558 | doi-access = free }}</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 bronchi and lungs.<ref>{{cite journal | vauthors = Miura T | title = Modeling lung branching morphogenesis | journal = Current Topics in Developmental Biology | volume = 81 | pages = 291–310 | date = 2008 | pmid = 18023732 | doi = 10.1016/S0070-2153(07)81010-6 | 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 | date = January 2015 | pmid = 25068457 | pmc = 4370254 | doi = 10.1165/rcmb.2014-0132TR }}</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 = 1611–1624 | date = May 2006 | pmid = 16613830 | doi = 10.1242/dev.02310 | s2cid = 18195361 | doi-access = free }}</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 (i.e., 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. By modulating retinoblastoma protein activity in rat cochlea, sonic hedgehog allows mature hair cells that normally cannot return to a proliferative state to divide and differentiate. Retinoblastoma proteins 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 = Biochemical and Biophysical Research Communications | volume = 430 | issue = 2 | pages = 700–705 | date = January 2013 | pmid = 23211596 | pmc = 3579567 | doi = 10.1016/j.bbrc.2012.11.088 }}</ref>

SHH is important for regulating dermal adipogenesis by hair follicle transit-amplifying cells (HF-TACs). Specifically, SHH induces dermal angiogenesis by acting directly on adipocyte precursors and promoting their proliferation through their expression of the peroxisome proliferator-activated receptor γ (Pparg) gene.<ref>{{cite journal | vauthors = Zhang B, Tsai PC, Gonzalez-Celeiro M, Chung O, Boumard B, Perdigoto CN, Ezhkova E, Hsu YC | title = Hair follicles' transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog | journal = Genes & Development | volume = 30 | issue = 20 | pages = 2325–2338 | date = October 2016 | pmid = 27807033 | pmc = 5110998 | doi = 10.1101/gad.285429.116 }}</ref>

== Processing ==
SHH undergoes a series of processing steps before it is secreted from the cell. Newly synthesised SHH weighs 45&nbsp;kDa and is referred to as the preproprotein. As a secreted protein, it contains a short 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 = Molecular and Cellular Biology | volume = 15 | issue = 4 | pages = 2294–2303 | date = 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 | vauthors = Ingham PW, Nakano Y, Seger C | title = Mechanisms and functions of Hedgehog signalling across the metazoa | journal = Nature Reviews. Genetics | volume = 12 | issue = 6 | pages = 393–406 | date = June 2011 | pmid = 21502959 | doi = 10.1038/nrg2984 | s2cid = 33769324 }}</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 | date = October 1996 | pmid = 8824192 | doi = 10.1126/science.274.5285.255 | s2cid = 11125394 | bibcode = 1996Sci...274..255P }}</ref> Thus, the C-terminal domain acts as an intein and a cholesterol transferase. Another hydrophobic moiety, a 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 membrane-bound O-acyltransferase family 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 = The Journal of Biological Chemistry | volume = 273 | issue = 22 | pages = 14037–14045 | date = May 1998 | pmid = 9593755 | doi = 10.1074/jbc.273.22.14037 | s2cid = 22783982 | doi-access = free }}</ref>

== Robotnikinin ==
A potential inhibitor of the Hedgehog signaling pathway has been found and dubbed "Robotnikinin"—after Sonic the Hedgehog's nemesis and the main antagonist of the Sonic the Hedgehog game series, 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 = Nature Chemical Biology | volume = 5 | issue = 3 | pages = 154–156 | date = March 2009 | pmid = 19151731 | pmc = 2770933 | doi = 10.1038/nchembio.142 }}</ref>

== Former 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 a few clinicians and scientists to criticize the name on the grounds that it sounds 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 | s2cid = 19861153 | doi-access = free | bibcode = 2006Natur.439..266M }}</ref><ref name="pmid16718675">{{cite journal | vauthors = Cohen MM | title = Problems in the naming of genes | journal = American Journal of Medical Genetics. Part A | volume = 140 | issue = 13 | pages = 1483–1484 | date = July 2006 | pmid = 16718675 | doi = 10.1002/ajmg.a.31264 | s2cid = 221388561 }}</ref> This controversy has largely died down, and the name is now generally seen as a humorous relic of the time before the rise of fast, cheap complete genome sequencing and standardized nomenclature.<ref>{{Cite web |url=https://psmag.com/environment/sonic-hedgehog-dicer-problem-naming-genes-91386 |title=Sonic Hedgehog, DICER, and the Problem With Naming Genes |vauthors=White M |date=September 26, 2014 |website=psmag.com |publisher=Pacific Standard |access-date=December 24, 2020 |archive-date=November 12, 2020 |archive-url=https://web.archive.org/web/20201112012239/https://psmag.com/environment/sonic-hedgehog-dicer-problem-naming-genes-91386 |url-status=live }}</ref> The problem of the "inappropriateness" of the names of genes such as "Mothers against decapentaplegic," "[[LFNG|Lunatic fringe]]," and "Sonic hedgehog" is largely avoided by using standardized abbreviations when speaking with patients and their families.<ref>{{cite journal |vauthors=Hopkin M |date=November 6, 2006 |title=Troublesome gene names get the boot |url=https://www.nature.com/news/2006/061106/full/news061106-2.html |journal=Nature |pages=news061106–2 |doi=10.1038/news061106-2 |s2cid=86514270 |access-date=December 24, 2020 |archive-date=December 31, 2020 |archive-url=https://web.archive.org/web/20201231153242/https://www.nature.com/news/2006/061106/full/news061106-2.html |url-status=live |doi-access=free |url-access=subscription }}</ref>

==Summary==
Sonic Hedgehog (SHH) is a signaling molecule that helps shape the spinal cord in early embryonic development. It establishes cell types based on a top-to-bottom pattern. In CNS development, SHH functions as a morphogen in the early stages of vertebrate ventral neural-tube development. Dorsoventral differentiation of neural tube cells is attributed to the secretion of SHH by the notochord. This secretion of SHH is what induces the differentiation of the floor plate. Another theory suggests that each of the notochord, floor plate, and endoderm can secrete SHH because of their shared origin in the Hensen's Node.  In vertebrates, such as mice, the Gli2 gene contributes greatly to expressing the SHH signaling pathway. Mice lacking the Gli2 gene show similar developmental defects to mice that are lacking the SHH gene. These defects include missing vertebrae and spinal disks. Since these two genes, when lacking, express similar defects, it is thought that the Gli gene is the primary transducer of SHH signaling. <ref>Fisher CE, Howie SEM, eds. Shh and Gli signalling and development. 1st ed. Springer; 2006:5-6. doi:10.1007/978-0-387-39957-7</ref>

==Gallery==

<gallery>
File:Shh and Gli proteins interactions.svg|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|Processing of SHH
File:sonichedgehog.svg|Concentration gradient of SHH
</gallery>

== 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 = 2031–2037 | date = July 2006 | pmid = 16687440 | doi = 10.1093/hmg/ddl123 | doi-access = free }}
* {{cite book | vauthors = Gilbert SF |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 = 306–315 | date = May 2001 | pmid = 11359461 | doi = 10.1034/j.1399-0004.2001.590503.x | s2cid = 34304310 }}
* {{cite journal | vauthors = Morton JP, Lewis BC | title = Shh signaling and pancreatic cancer: implications for therapy? | journal = Cell Cycle | volume = 6 | issue = 13 | pages = 1553–1557 | date = July 2007 | pmid = 17611415 | doi = 10.4161/cc.6.13.4467 | s2cid = 4670615 | doi-access = free }}
* {{cite journal | vauthors = Mullor JL, Sánchez P, Ruiz i Altaba A | title = Pathways and consequences: Hedgehog signaling in human disease | journal = Trends in Cell Biology | volume = 12 | issue = 12 | pages = 562–569 | date = December 2002 | 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 | date = July 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 = 1137–1145 | date = December 2005 | pmid = 16300466 | doi = 10.1517/14728222.9.6.1137 | s2cid = 5548531 }}

{{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
* [https://web.archive.org/web/20080724170643/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