Sonic hedgehog

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For the video game character and its namesake, see Sonic the Hedgehog (character).
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File:SHH location.png
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 mammalian signaling pathway family called hedgehog, the others being desert hedgehog (DHH) and Indian hedgehog (IHH). SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as in the growth of digits on limbs and organization of the brain. Sonic hedgehog is the best established example of a 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 and name

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.[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 the spines 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.[3][4][5][6] Two of these, desert hedgehog and Indian hedgehog, were named for species of hedgehogs, while sonic hedgehog was named after Sonic the Hedgehog, the protagonist of the eponymous video game franchise.[7][8] The name was devised by Robert Riddle, who was a postdoctoral fellow at the Tabin Lab, after he saw a Sonic comic his daughter had brought from England.[9][10] In the zebrafish, two of the three vertebrate hh genes are duplicated: SHH a,[11] SHH b[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 echidna character Knuckles 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 limb[5] and midline structures in the brain,[14][15] spinal cord,[16] the thalamus by the zona limitans intrathalamica[17][18] the lungs,[19] and the teeth.[20] 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,[21] and medulloblastoma,[22] as well as the progression of prostate cancer tumours.[23] For SHH to be expressed in the developing embryo limbs, a morphogen called fibroblast growth factors must be secreted from the apical ectodermal ridge.[24]

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.[25] Specifically, SHH attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations.[26] The absence (non-expression) of SHH has been shown to control the growth of nascent hind limbs in cetaceans[27] (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.[28] 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.[29] 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.[30]

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.[31]

Sonic hedgehog is the secreted protein which mediates signaling activities of the notochord and floor plate.[32] Studies involving ectopic expression of SHH in vitro[33] and in vivo[34] 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.[35]In vitro blocking of SHH signaling using antibodies against it shows similar phenotypes.[34] SHH exerts its effects in a concentration-dependent manner,[36] so that a high concentration of SHH results in a local inhibition of cellular proliferation.[37] 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.[34] Once the floor plate is established, cells residing in this region will subsequently express SHH themselves[37] 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[38] throughout the ventral neural tube.[39] 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.[40] 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.[41] 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.[42] In vertebrates three different Gli proteins are present, viz. Gli1, Gli2 and Gli3, which are expressed in the neural tube.[43] Mice mutant for Gli1 show normal spinal cord development, suggesting that it is dispensable for mediating SHH activity.[44] However Gli2 mutant mice show abnormalities in the ventral spinal cord with severe defects in the floor plate and ventral-most interneurons (V3).[45] Gli3 antagonizes SHH function in a dose dependent manner, promoting dorsal neuronal subtypes. SHH mutant phenotype can be rescued in SHH/Gli3 double mutant.[46] Gli proteins have a C-terminal activation domain and an N-terminal repressive domain.[43][47]

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.[46] 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.[46][48]

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.[49] Vitronectin is another protein that is induced by SHH; it acts as an obligate co-factor for SHH signaling in the neural tube.[50]

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).[40] 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.[37] 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.[51]

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.[52] 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.[53] 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.[54] 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.[55] 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.[55] 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.[56]

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.[55] 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.[55]

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.[55] 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.[55] The expression of Olig2 rapidly expands in a dorsal direction concomitantly with the continuous dorsal extension of the SHH gradient over time.[55] 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.,[55] 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.[55] 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]

Lung development

Although SHH is most commonly associated with brain and limb digit development, it is also important in lung development.[61][62][63][64] 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.[65][66] SHH expressed throughout the foregut endoderm (innermost of three germ layers) in the distal epithelium where the embryonic lungs are developing.[63][66] 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.[63][66] Mice who are deficient in SHH can develop tracheoesophageal fistula (abnormal connection of the esophagus and trachea).[67][63] Additionally, it a double (SHH-/- ) knockout mouse model exhibited poor lung development. The lungs of the SHH double knockout failed to undergo lobation and branching (the abnormal lungs only developed one branch compared to an extensively branched phenotype of the wildtype).[63]

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.[68]

Processing

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.[69] 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.[70][71] 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.[72]

Robotnikinin

A potential inhibitor of the Hedgehog signaling pathway has been found and dubbed "Robotnikinin", in honour of Sonic the Hedgehog's nemesis, Dr. Ivo "Eggman" Robotnik.[73]

Controversy surrounding name

The gene has been linked to a condition known as holoprosencephaly, which can result in severe brain, skull and facial defects, possibly causing clinicians and scientists to criticize the name on the grounds of it sounding too frivolous. It has been noted that mention of a mutation in a sonic hedgehog gene might not be well received in a discussion of a serious disorder with a patient or their family. [9][74][75]

Gallery

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

See also

References

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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. doi:10.1093/hmg/ddl123. PMID 16687440.
  • Gilbert, Scott F. (2000). Developmental biology (6th ed.). Sunderland, Mass: Sinauer Associates. ISBN 0-87893-243-7.
  • Kim J, Kim P, Hui CC (2001). "The VACTERL association: lessons from the Sonic hedgehog pathway". Clinical Genetics. 59 (5): 306–15. doi:10.1034/j.1399-0004.2001.590503.x. PMID 11359461.
  • Morton JP, Lewis BC (2007). "SHH signaling and pancreatic cancer: implications for therapy?". Cell Cycle. 6 (13): 1553–7. doi:10.4161/cc.6.13.4467. PMID 17611415.
  • Mullor JL, Sánchez P, Ruiz i Altaba A (2003). "Pathways and consequences: Hedgehog signaling in human disease". Trends Cell Biol. 12 (12): 562–9. doi:10.1016/S0962-8924(02)02405-4. PMID 12495844.
  • 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. doi:10.1002/1096-8628(20010722)102:13.0.CO;2-U. PMID 11471164.
  • Williams JA (2006). "Hedgehog and spinal cord injury". Expert Opinion on Therapeutic Targets. 9 (6): 1137–45. doi:10.1517/14728222.9.6.1137. PMID 16300466.

External links

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