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Sonic hedgehog


Sonic hedgehog

Sonic hedgehog
3D structure of the signaling domain of the murine Sonic hedgehog from ​
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search
SHH gene is located on the long (q) arm of chromosome 7 at position 36.

Sonic hedgehog is a protein that in humans is encoded by the SHH ("sonic hedgehog") gene.[1] Both the gene and the protein may also be found notated alternatively as "Shh".

Sonic hedgehog is one of three proteins in the morphogen as defined by Lewis Wolpert's French flag model—a molecule that diffuses to form a concentration gradient and has different effects on the cells of the developing embryo depending on its concentration. SHH remains important in the adult. It controls cell division of adult stem cells and has been implicated in the development of some cancers.


  • Discovery 1
  • Function 2
    • Patterning of the central nervous system 2.1
    • Morphogenetic activity 2.2
    • Tooth development 2.3
    • Potential Regenerative Function 2.4
  • Processing 3
  • Robotnikinin 4
  • Controversy surrounding name 5
  • Gallery 6
  • See also 7
  • References 8
  • Further reading 9
  • External links 10


The hedgehog gene (hh) was first identified in the fruit-fly Drosophila melanogaster in the classic Heidelberg screens of Christiane Nusslein-Volhard and Eric Wieschaus, as published in 1980.[2] These screens, which led to them winning the 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 (small pointy projections), resembling a hedgehog.

Investigations aimed at finding a hedgehog equivalent in vertebrates by [12] (formerly described as tiggywinkle hedgehog named for Mrs. Tiggy-Winkle, a character from Beatrix Potter's books for children), ihha and ihhb[13] (formerly described as echidna hedgehog, named for the spiny anteater and not for the Sonic character).


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 limb[5] and midline structures in the brain,[14][15] spinal cord,[16] the thalamus by the zona limitans intrathalamica[17][18] and the teeth.[19] Mutations in the human sonic hedgehog gene, SHH, cause holoprosencephaly type 3 HPE3 as a result of the loss of the ventral midline. Sonic hedgehog is secreted at the zone of polarizing activity, which is located on the posterior side of a limb bud in an embryo. The sonic hedgehog transcription pathway has also been linked to the formation of specific kinds of cancerous tumors, including the embryonic cerebellar tumor, medulloblastoma.[20][20][21] For SHH to be expressed in a developing embryo, a related morphogen called fibroblast growth factors must be secreted from the apical ectodermal ridge.[22]

More recently, 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.[23] Specifically, SHH attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations.[24] The absence (non-expression) of SHH has been shown to control the growth of nascent hind limbs in cetaceans[25] (whales and dolphins).

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.[26] 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.[27] 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.[28]

The neural tube itself is the initial groundwork of the 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.[29]

morphogens that pattern the dorsoventral axes of the neural tube
SHH and BMP gradients in the vertebrate neural tube 
Depiction of the formation of an ectopic floor plate within the neural tube in the presence of a second notochord
Ectopic floor plate formation 
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.[30] Studies involving ectopic expression of SHH in vitro[31] and in vivo[32] result in floor plate induction, and differentiation of motor neuron and ventral interneurons. On the other hand, mice mutant for SHH lack ventral spinal cord characteristics.[33]In vitro blocking of SHH signaling using antibodies against it shows similar phenotypes.[32] SHH exerts its effects in a concentration-dependent manner,[34] so that a high concentration of SHH results in a local inhibition of cellular proliferation.[35] 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.[32] Once the floor plate is established, cells residing in this region will subsequently express SHH themselves[35] 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[36] throughout the ventral neural tube.[37] 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.[38] 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.[39] 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.[40] In vertebrates three different Gli proteins are present, viz. Gli1, Gli2 and Gli3, which are expressed in the neural tube.[41] Mice mutant for Gli1 show normal spinal cord development, suggesting that it is dispensable for mediating SHH activity.[42] However Gli2 mutant mice show abnormalities in the ventral spinal cord with severe defects in the floor plate and ventral-most interneurons (V3).[43] Gli3 antagonizes SHH function in a dose dependent manner, promoting dorsal neuronal subtypes. SHH mutant phenotype can be rescued in SHH/Gli3 double mutant.[44] Gli proteins have a C-terminal activation domain and an N-terminal repressive domain.[41][45]

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.[44] 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.[44][46]

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.[47] Vitronectin is another protein that is induced by SHH; it acts as an obligate co-factor for SHH signaling in the neural tube.[48]

There are five distinct progenitor domains in the ventral neural tube, viz. V3 interneuron, motor neurons (MN), V2, V1, and V0 interneurons (in ventral to dorsal order).[38] 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.[35] 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.[49]

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 which ventralize the fate of the neural plate cell for a given SHH concentration.[50] On the other hand, mutation in BMP antagonists (such as noggin) produces severe defects in ventral-most characteristics of the spinal cord followed by ectopic expression of BMP in the ventral neural tube.[51] 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.[52] 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.[53] 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.[53] 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.[54]

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.[55][56] 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.[53] 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.[53]

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.[53] 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.[53] The expression of Olig2 rapidly expands in a dorsal direction concomitantly with the continuous dorsal extension of the SHH gradient over time.[53] 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.,[53] 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.[53] 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.[57]

Tooth development

Sonic hedgehog (SHH) is a signaling molecule that is encoded by the same gene sonic hedgehog. SHH plays 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.[58] 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.[59] 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.[60]

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.[61]


SHH undergoes a series of processing steps before it is secreted from the cell. Newly synthesised SHH weighs 45 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 kDa N-terminal signaling domain (SHH-N) and a 25 kDa C-terminal domain with no known signaling role.[62] 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.[63] 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.[64]


A potential inhibitor of the Hedgehog signaling pathway has been found and dubbed 'Robotnikinin', in honor of Sonic the Hedgehog's nemesis, Dr. Ivo "Eggman" Robotnik.[65]

Controversy surrounding name

The gene has already been linked to a condition known as holoprosencephaly, which can result in severe brain, skull and facial defects; motivation for some clinicians and scientists to criticize the name on grounds of it sounding too frivolous. They point to a less humorous situation where patients or parents of patients with a serious disorder are told that they or their child "have a mutation in [their] sonic hedgehog".[9][66][67]


SHH gradient and Gli activity in the vertebrate neural tube.
Processing of SHH

See also


  1. ^ Marigo V, Roberts DJ, Lee SM, Tsukurov O, Levi T, Gastier JM, Epstein DJ, Gilbert DJ, Copeland NG, Seidman CE (July 1995). "Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog". Genomics 28 (1): 44–51.  
  2. ^ Nüsslein-Volhard C, Wieschaus E (October 1980). "Mutations affecting segment number and polarity in Drosophila". Nature 287 (5785): 795–801.  
  3. ^ Krauss S, Concordet JP, Ingham PW (December 1993). "A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos". Cell 75 (7): 1431–44.  
  4. ^ Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP (December 1993). "Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity". Cell 75 (7): 1417–30.  
  5. ^ a b Riddle RD, Johnson RL, Laufer E, Tabin C (1993). "Sonic hedgehog mediates the polarizing activity of the ZPA". Cell 75 (7): 1401–16.  
  6. ^ Angier N (1994-01-11). "Biologists Find Key Genes That Shape Patterning of Embryos". Science. New York Times. 
  7. ^  
  8. ^ Tom Simonite (2005-12-15). "Pokémon blocks gene name" 438 (897). Nature.  
  9. ^ a b "A Gene Named Sonic". The New York Times. 1994-01-11. 
  10. ^ Annalise Keen and Cliff Tabin (April 12, 2004). "Cliff Tabin: Super Sonic An Interview". The Weekly Murmur. 
  11. ^ "Zebrafish SHHa". University of Oregon. 
  12. ^ "Zebrafish SHHb". University of Oregon. 
  13. ^ Currie PD, Ingham PW (August 1996). "Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish". Nature 382 (6590): 452–5.  
  14. ^ Herzog W, Zeng X, Lele Z, Sonntag C, Ting JW, Chang CY, Hammerschmidt M (February 2003). "Adenohypophysis formation in the zebrafish and its dependence on sonic hedgehog". Dev. Biol. 254 (1): 36–49.  
  15. ^ Rash BG, Grove EA (Oct 2007). "Patterning the dorsal telencephalon: a role for sonic hedgehog?". The Journal of Neuroscience 27 (43): 11595–603.  
  16. ^ Lewis KE, Eisen JS (September 2001). "Hedgehog signaling is required for primary motoneuron induction in zebrafish". Development 128 (18): 3485–95.  
  17. ^ Scholpp S, Wolf O, Brand M, Lumsden A (March 2006). "Hedgehog signalling from the zona limitans intrathalamica orchestrates patterning of the zebrafish diencephalon". Development 133 (5): 855–64.  
  18. ^ Rash BG, Grove EA (Nov 2011). "Shh and Gli3 regulate formation of the telencephalic-diencephalic junction and suppress an isthmus-like signaling source in the forebrain". Developmental Biology 359 (2): 242–50.  
  19. ^ Dassule HR, Lewis P, Bei M, Maas R, McMahon AP (November 2000). "Sonic hedgehog regulates growth and morphogenesis of the tooth" (PDF). Development 127 (22): 4775–85.  
  20. ^ a b Taylor, Michael D.; Northcott, Paul A.; Korshunov, Andrey; Remke, Marc; Cho, Yoon-Jae; Clifford, Steven C.; Eberhart, Charles G.; Parsons, D. Williams; Rutkowski, Stefan; Gajjar, Amar; Ellison, David W.; Lichter, Peter; Gilbertson, Richard J.; Pomeroy, Scott L.; Kool, Marcel; Pfister, Stefan M. (2 December 2011). "Molecular subgroups of medulloblastoma: the current consensus". Acta Neuropathologica 123 (4): 465–472.  
  21. ^ DeSouza, Ruth-Mary; Jones, Benjamin R. T.; Lowis, Stephen P.; Kurian, Kathreena M. (22 July 2014). "Pediatric Medulloblastoma â€" Update on Molecular Classification Driving Targeted Therapies". Frontiers in Oncology 4.  
  22. ^ Tabin C, Riddle R (February 1999). "How Limbs Develop". Scientific American: 78. 
  23. ^ Charron F, Stein E, Jeong J, McMahon AP, Tessier-Lavigne M (2003). "The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance". Cell 113 (1): 11–23.  
  24. ^ Kolpak A, Zhang J, Bao ZZ (March 2005). "Sonic hedgehog has a dual effect on the growth of retinal ganglion axons depending on its concentration". J. Neurosci. 25 (13): 3432–41.  
  25. ^ Thewissen JG, Cohn MJ, Stevens LS, Bajpai S, Heyning J, Horton WE (May 2006). "Developmental basis for hind-limb loss in dolphins and origin of the cetacean bodyplan". Proc. Natl. Acad. Sci. U.S.A. 103 (22): 8414–8.  
  26. ^ Litingtung Y, Chiang C (October 2000). "Control of SHH activity and signaling in the neural tube". Developmental Dynamics 219 (2): 143–54.  
  27. ^ Placzek M (August 1995). "The role of the notochord and floor plate in inductive interactions". Current Opinion in Genetics & Development 5 (4): 499–506.  
  28. ^ Teillet MA, Lapointe F, Le Douarin NM (September 1998). "The relationships between notochord and floor plate in vertebrate development revisited.". Proceedings of the National Academy of Sciences USA 95 (20): 11733–8.  
  29. ^ van Straaten HW, Hekking JW, Thors F, Wiertz-Hoessels EL, Drukker J (October 1985). "Induction of an additional floor plate in the neural tube". Acta Morphol Neerl Scand 23 (2): 91–7.  
  30. ^ Patten I and Placzek M (2000). Cellular and Molecular Life Sciences 57. pp. 1695–1708.  
  31. ^ Martí E, Bumcrot DA, Takada R, McMahon AP (May 1995). "Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants.". Nature 375 (6529): 322–325.  
  32. ^ a b c Ericson J, Morton S, Kawakami A, Roelink H, Jessell TM (November 1996). "Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity". Cell 87 (4): 661–73.  
  33. ^ Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA (October 1996). "Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function". Nature 383 (6599): 407–13.  
  34. ^ Placzek M, Tessier-Lavigne M, Yamada T, Jessell T, Dodd J (November 1990). "Mesodermal control of neural cell identity: floor plate induction by the notochord". Science 250 (4983): 985–8.  
  35. ^ a b c Wilson L, Maden M (June 2005). "The mechanisms of dorsoventral patterning in the vertebrate neural tube". Dev. Biol. 282 (1): 1–13.  
  36. ^ 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 (November 1996). "The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog.". Nature. 384 (6605): 129–34.  
  37. ^ Marigo V, Tabin CJ (1996). "Regulation of patched by sonic hedgehog in the developing neural tube". Proc. Natl. Acad. Sci. U.S.A. 93 (18): 9346–51.  
  38. ^ a b Ericson J, Briscoe J, Rashbass P, van Heyningen V, Jessell TM (1997). "Graded sonic hedgehog signaling and the specification of cell fate in the ventral neural tube.". Cold Spring Harb Symp Quant Biol. 62: 451–66.  
  39. ^ Ericson J, Rashbass P, Schedl A, Brenner-Morton S, Kawakami A, van Heyningen V, Jessell TM, Briscoe J (July 1997). "Pax6 controls progenitor cell identity and neuronal fate in response to graded SHH signaling.". Cell 90 (1): 169–80.  
  40. ^ Lum L, Beachy PA (June 2004). "The Hedgehog response network: sensors, switches, and routers.". Science 304 (5678): 1755–9.  
  41. ^ a b Ruiz i Altaba A (June 1998). "Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog". Development 125 (12): 2203–12.  
  42. ^ Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M, Joyner AL (April 2000). "Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.". Development 127 (8): 1593–605.  
  43. ^ Matise MP, Epstein DJ, Park HL, Platt KA, Joyner AL (August 1998). "Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system.". Development 125 (15): 2759–70.  
  44. ^ a b c Litingtung Y, Chiang C (October 2000). "Specification of ventral neuron types is mediated by an antagonistic interaction between SHH and Gli3.". Nat Neurosci 3 (10): 979–85.  
  45. ^ Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H (September 1999). "Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of SHH signaling.". Development 126 (17): 3915–24.  
  46. ^ Persson M, Stamataki D, te Welscher P, Andersson E, Böse J, Rüther U, Ericson J, Briscoe J (November 2002). "Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity.". Genes Dev 16 (22): 2865–78.  
  47. ^ Chuang PT, McMahon AP (February 1999). "Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein.". Nature 397 (6720): 617–21.  
  48. ^ Pons S, Martí E (January 2000). "Sonic hedgehog synergizes with the extracellular matrix protein vitronectin to induce spinal motor neuron differentiation.". Development 127 (2): 333–42.  
  49. ^ Briscoe J, Pierani A, Jessell TM, Ericson J (May 2000). "A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube.". Cell 101 (4): 435–45.  
  50. ^ Liem KF, Jessell TM, Briscoe J (November 2000). "Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites.". Development 127 (22): 4855–66.  
  51. ^ McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP (May 1998). "Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite.". Genes Dev 12 (10): 1438–52.  
  52. ^ a b c d e f g h i
  53. ^ Chamberlain CE, Jeong J, Guo C, Allen BL, McMahon AP (March 2008). "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". Development 135 (6): 1097–1106.  
  54. ^ Ribes V, Briscoe J (August 2009). "Establishing and interpreting Graded Sonic Hedgehog during Vertebrate Neural Tube Patterning: The Role of Negative Feedback". Cold Spring Harb Perspect Biol. 1(2): a002014 (2): a002014.  
  55. ^
  56. ^ Lovrics A, Gao Y, Juhász B, Bock I, Byrne HM, Dinnyés A, Kovács KA (November 2014). "Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord". PLoS One 9 (11): 11430.  
  57. ^ Nanci, Antonio (2012). Ten Cate's Oral Histology (8 ed.). 
  58. ^ Thesleff I (2003). "Epithelial-mesenchymal signalling regulating tooth morphogenesis". J. Cell. Sci. 116 (Pt 9): 1647–8.  
  59. ^ Hardcastle Z, Mo R, Hui CC, Sharpe PT (1998). "The SHH signalling pathway in tooth development: defects in Gli2 and Gli3 mutants". Development 125 (15): 2803–11.  
  60. ^ Lu N, Chen Y, Wang Z, Chen G, Lin Q, Chen ZY, Li H (2013). "Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein". Biochem. Biophys. Res. Commun. 430 (2): 700–5.  
  61. ^ Bumcrot DA, Takada R, McMahon AP (1 April 1995). "Proteolytic processing yields two secreted forms of sonic hedgehog". Mol Cell Biol. 15 (4): 2294–2303.  
  62. ^ Porter JA, Young KE, Beachy PA (1996). "Cholesterol modification of hedgehog signaling proteins in animal development". Science 274 (5285): 255–259.  
  63. ^ 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 (1998). "Identification of a palmitic acid-modified form of human Sonic hedgehog". J Biol Chem 273 (22): 14037–14045.  
  64. ^ 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 (March 2009). "A small molecule that binds Hedgehog and blocks its signaling in human cells". Nat. Chem. Biol. 5 (3): 154–6.  
  65. ^ Maclean K (January 2006). "Humour of gene names lost in translation to patients". Nature 439 (7074): 266.  
  66. ^ Cohen MM (July 2006). "Problems in the naming of genes". Am. J. Med. Genet. A 140 (13): 1483–4.  

Further reading

  • Dorus S, Anderson JR, Vallender EJ, Gilbert SL, Zhang L, Chemnick LG, Ryder OA, Li W, Lahn BT (2006). "Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates". Human Molecular Genetics 15 (13): 2031–7.  
  • Gilbert, Scott F. (2000). Developmental biology (6th ed.). Sunderland, Mass: Sinauer Associates.  
  • Kim J, Kim P, Hui CC (2001). "The VACTERL association: lessons from the Sonic hedgehog pathway". Clinical Genetics 59 (5): 306–15.  
  • Morton JP, Lewis BC (2007). "SHH signaling and pancreatic cancer: implications for therapy?". Cell Cycle 6 (13): 1553–7.  
  • Mullor JL, Sánchez P, Ruiz i Altaba A (2003). "Pathways and consequences: Hedgehog signaling in human disease". Trends Cell Biol. 12 (12): 562–9.  
  • Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M (2001). "SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature". American Journal of Medical Genetics 102 (1): 1–10.  
  • Williams JA (2006). "Hedgehog and spinal cord injury". Expert Opinion on Therapeutic Targets 9 (6): 1137–45.  

External links

  • SHHAn introductory article on at Davidson College
  • 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
  • ‘Sonic Hedgehog’ sounded funny, at first. New York Times, November 12, 2006.
  • GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
  • SHH – sonic hedgehog US National Library of Medicine
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