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Sonic hedgehog protein – Wikipedia

Sonic hedgehog protein – Wikipedia

2023-01-26 15:06:49

Signaling molecule in animals

Shh structure.png
Aliases SHH, HHG1, HLP3, HPE3, MCOPCB5, SMMCI, TPT, TPTPS, sonic hedgehog, Sonic hedgehog, ShhNC, sonic hedgehog signaling molecule
Exterior IDs OMIM: 600725 MGI: 98297 HomoloGene: 30961 GeneCards: SHH

Sonic hedgehog protein (SHH) is encoded for by the SHH gene.[5] The protein is known as after the character Sonic the Hedgehog.

This signaling molecule is vital in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and the group of the central nervous system, limbs, digits and lots of different components of the physique. Sonic hedgehog is a morphogen that patterns the creating embryo utilizing a focus gradient characterised by the French flag model.[6] This mannequin has a non-uniform distribution of SHH molecules which governs totally different cell fates in response to focus. Mutations on this gene may cause holoprosencephaly, a failure of splitting within the cerebral hemispheres,[7] as demonstrated in an experiment utilizing SHH knock-out mice by which the forebrain midline didn’t develop and as a substitute solely a single fused telencephalic vesicle resulted.[8]

Sonic hedgehog nonetheless performs a job in differentiation, proliferation, and upkeep of grownup tissues. Irregular activation of SHH signaling in grownup tissues has been implicated in numerous forms of cancers together with breast, skin, brain, liver, gallbladder and lots of extra.[9]

Discovery and naming[edit]

The hedgehog gene (hh) was first recognized within the fruit fly Drosophila melanogaster within the traditional Heidelberg screens of Christiane Nüsslein-Volhard and Eric Wieschaus, as revealed in 1980.[10] These screens, which led to the researchers successful a Nobel Prize in 1995 together with developmental geneticist Edward B. Lewis, recognized genes that management the segmentation sample of the Drosophila embryos. The hh lack of perform mutant phenotype causes the embryos to be coated with denticles, i.e. small pointy projections resembling the spikes of a hedgehog. Investigations geared toward discovering a hedgehog equal in vertebrates by Philip Ingham, Andrew P. McMahon and Clifford Tabin revealed three homologous genes.[11][12][13][14]

Two of those genes, desert hedgehog and Indian hedgehog, have been named for species of hedgehogs, whereas sonic hedgehog was named after the online game character Sonic the Hedgehog.[15][16] The gene was named by Robert Riddle, a postdoctoral fellow on the Tabin Lab, after his spouse Betsy Wilder got here residence with {a magazine} containing an advert for the sport Sonic the Hedgehog.[17][18][19] Within the zebrafish, two of the three vertebrate hh genes are duplicated: SHH a[20] and SHH b[21] (previously described as tiggywinkle hedgehog, named for Mrs. Tiggy-Winkle, a personality from Beatrix Potter‘s books for kids) and ihha and ihhb[22] (previously described as echidna hedgehog, named for the spiny anteater and never for the character Knuckles the Echidna within the Sonic franchise).


Of the hh homologues, SHH has been discovered to have probably the most vital roles in growth, performing as a morphogen concerned in patterning many methods—together with the anterior pituitary,[23] pallium of the mind,[24] spinal cord,[25] lungs,[26] enamel[27] and the thalamus by the zona limitans intrathalamica.[28][29] In vertebrates, the development of limbs and digits will depend on the secretion of sonic hedgehog by the zone of polarizing activity, situated on the posterior facet of the embryonic limb bud.[13] Mutations within the human sonic hedgehog gene SHH trigger holoprosencephaly sort 3 HPE3, because of the lack of the ventral midline. The sonic hedgehog transcription pathway has additionally been linked to the formation of particular sorts of cancerous tumors, together with the embryonic cerebellar tumor[30] and medulloblastoma,[31] in addition to the development of prostate cancer tumours.[32] For SHH to be expressed within the creating embryo limbs, a morphogen referred to as fibroblast growth factors have to be secreted from the apical ectodermal ridge.[33]

Sonic hedgehog has additionally been proven to behave as an axonal guidance cue. It has been demonstrated that SHH attracts commissural axons on the ventral midline of the creating spinal twine.[34] Particularly, SHH attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at greater concentrations.[35] The absence (non-expression) of SHH has been proven to regulate the expansion of nascent hind limbs in cetaceans[36] (whales and dolphins).

The SHH gene is a member of the hedgehog gene household with 5 variations of DNA sequence alterations or splice variants.[37] SHH is situated on chromosome seven and initiates the manufacturing of Sonic Hedgehog protein.[37] This protein sends short- and long-range indicators to embryonic tissues to manage growth.[38] If the SHH gene is mutated or absent, the protein Sonic Hedgehog can not do its job correctly. Sonic hedgehog contributes to cell development, cell specification and formation, structuring and group of the physique plan.[39] This protein capabilities as a significant morphogenic signaling molecule and performs an essential function within the formation of many various buildings in creating embryos.[39] The SHH gene impacts a number of main organ methods, such because the nervous system, cardiovascular system, respiratory system and musculoskeletal system.[37][38] Mutations within the SHH gene may cause malformation of parts of those methods, which can lead to main issues within the creating embryo. The mind and eyes, for instance, may be considerably impacted by mutations on this gene and trigger issues comparable to Microphthalmia and Holoprosencephaly.[39] Microphthalmia is a situation that impacts the eyes, which leads to small, underdeveloped tissues in a single or each eyes.[39] This could result in points starting from a coloboma to a single small eye to the absence of eyes altogether.[38] Holoprosencephaly is a situation mostly brought on by a mutation of the SHH gene that causes improper separation of the left and proper mind and facial dysmorphia.[38][39] Many methods and buildings rely closely on correct expression of the SHH gene and subsequent sonic hedgehog protein, incomes it the excellence of being an important gene to growth.

Patterning of the central nervous system[edit]

The sonic hedgehog (SHH) signaling molecule assumes numerous roles in patterning the central nervous system (CNS) throughout vertebrate development. One of the vital characterised capabilities of SHH is its function within the induction of the floor plate and various ventral cell sorts throughout the neural tube.[40] The notochord—a construction derived from the axial mesoderm—produces SHH, which travels extracellularly to the ventral area of the neural tube and instructs these cells to type the ground plate.[41] One other view of flooring plate induction hypothesizes that some precursor cells situated within the notochord are inserted into the neural plate earlier than its formation, later giving rise to the ground plate.[42]

The neural tube itself is the preliminary groundwork of the vertebrate CNS, and the floor plate is a specialised construction, situated on the ventral midpoint of the neural tube. Proof supporting the notochord because the signaling heart comes from research by which a second notochord is implanted close to a neural tube in vivo, resulting in the formation of an ectopic flooring plate throughout the neural tube.[43]

Sonic hedgehog is the secreted protein that mediates signaling actions of the notochord and flooring plate.[44] Research involving ectopic expression of SHH in vitro[45] and in vivo[46] end in flooring plate induction and differentiation of motor neuron and ventral interneurons. Then again, mice mutants for SHH lack ventral spinal twine traits.[47] In vitro blocking of SHH signaling utilizing antibodies in opposition to it reveals related phenotypes.[46] SHH exerts its results in a concentration-dependent method,[48] so {that a} excessive focus of SHH ends in an area inhibition of cellular proliferation.[49] This inhibition causes the ground plate to turn into skinny in comparison with the lateral areas of the neural tube. Decrease focus of SHH ends in mobile proliferation and induction of varied ventral neural cell sorts.[46] As soon as the floor plate is established, cells residing on this area will subsequently categorical SHH themselves,[49] producing a concentration gradient throughout the neural tube.

Though there isn’t a direct proof of a SHH gradient, there’s oblique proof by way of the visualization of Patched (Ptc) gene expression, which encodes for the ligand binding area of the SHH receptor[50] all through the ventral neural tube.[51] In vitro research present that incremental two- and threefold modifications in SHH focus give rise to motor neuron and totally different interneuronal subtypes as discovered within the ventral spinal twine.[52] These incremental modifications in vitro correspond to the gap of domains from the signaling tissue (notochord and flooring plate) which subsequently differentiates into totally different neuronal subtypes because it happens in vitro.[53] Graded SHH signaling is usually recommended to be mediated by means of the Gli household of proteins, that are vertebrate homologues of the Drosophila zinc-finger-containing transcription factor Cubitus interruptus (Ci). Ci is an important mediator of hedgehog (Hh) signaling in Drosophila.[54] In vertebrates, three totally different Gli proteins are current, viz. Gli1, Gli2 and Gli3, that are expressed within the neural tube.[55] Mice mutants for Gli1 present regular spinal twine growth, suggesting that it’s dispensable for mediating SHH exercise.[56] Nonetheless, Gli2 mutant mice present abnormalities within the ventral spinal twine, with extreme defects within the flooring plate and ventral-most interneurons (V3).[57] Gli3 antagonizes SHH perform in a dose-dependent method, selling dorsal neuronal subtypes. SHH mutant phenotypes may be rescued in a SHH/Gli3 double mutant.[58] Gli proteins have a C-terminal activation area and an N-terminal repressive area.[55][59]

SHH is usually recommended to advertise the activation perform of Gli2 and inhibit repressive exercise of Gli3. SHH additionally appears to advertise the activation perform of Gli3, however this exercise isn’t robust sufficient.[58] The graded focus of SHH offers rise to graded exercise of Gli 2 and Gli3, which promote ventral and dorsal neuronal subtypes within the ventral spinal twine. Proof from Gli3 and SHH/Gli3 mutants present that SHH primarily regulates the spatial restriction of progenitor domains fairly than being inductive, as SHH/Gli3 mutants present intermixing of cell sorts.[58][60]

SHH additionally induces different proteins with which it interacts, and these interactions can affect the sensitivity of a cell in the direction of SHH. Hedgehog-interacting protein (HHIP) is induced by SHH, which in flip attenuates its signaling exercise.[61] Vitronectin is one other protein that’s induced by SHH; it acts as an obligate co-factor for SHH signaling within the neural tube.[62]

There are 5 distinct progenitor domains within the ventral neural tube: V3 interneurons, motor neurons (MN), V2, V1, and V0 interneurons (in ventral to dorsal order).[52] These totally different progenitor domains are established by “communication” between totally different courses of homeobox transcription factors. (See Trigeminal Nerve.) These transcription factors reply to SHH gradient focus. Relying upon the character of their interplay with SHH, they’re labeled into two teams—class I and sophistication II—and are composed of members from the Pax, Nkx, Dbx and Irx households.[49] Class I proteins are repressed at totally different thresholds of SHH delineating ventral boundaries of progenitor domains, whereas class II proteins are activated at totally different thresholds of SHH delineating the dorsal restrict of domains. Selective cross-repressive interactions between class I and sophistication II proteins give rise to 5 cardinal ventral neuronal subtypes.[63]

It is very important notice that SHH isn’t the one signaling molecule exerting an impact on the creating neural tube. Many different molecules, pathways and mechanisms are lively (e.g., RA, FGF, BMP), and sophisticated interactions between SHH and different molecules are potential. BMPs are urged to play a vital function in figuring out the sensitivity of neural cell to SHH signaling. Proof supporting this comes from research utilizing BMP inhibitors that ventralize the destiny of the neural plate cell for a given SHH focus.[64] Then again, mutation in BMP antagonists (e.g., noggin) produces extreme defects within the ventral-most traits of the spinal twine, adopted by ectopic expression of BMP within the ventral neural tube.[65] Interactions of SHH with Fgf and RA haven’t but been studied in molecular element.

Morphogenetic exercise[edit]

The concentration- and time-dependent, cell-fate-determining exercise of SHH within the ventral neural tube makes it a first-rate instance of a morphogen. In vertebrates, SHH signaling within the ventral portion of the neural tube is most notably chargeable for the induction of floor plate cells and motor neurons.[66] SHH emanates from the notochord and ventral flooring plate of the creating 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 chord.[67][68] Greater concentrations of the SHH ligand are present in probably the most ventral features of the neural tube and notochord, whereas decrease concentrations are discovered within the extra dorsal areas of the neural tube.[67] The SHH focus gradient has been visualized within the neural tube of mice engineered to precise a SHH::GFP fusion protein to indicate this graded distribution of SHH through the time of ventral neural tube patterning.[69]

It’s thought that the SHH gradient works to elicit a number of totally different cell fates by a concentration- and time-dependent mechanism that induces quite a lot of transcription elements within the ventral progenitor cells.[67][69] Every of the ventral progenitor domains expresses a extremely individualized mixture of transcription elements—Nkx2.2, Olig2, Nkx6.1, Nkx6.2, Dbx1, Dbx2, Irx3, Pax6, and Pax7—that’s regulated by the SHH gradient. These transcription elements are induced sequentially alongside the SHH focus gradient with respect to the quantity and time of publicity to SHH ligand.[67] As every inhabitants of progenitor cells responds to the totally different ranges of SHH protein, they start to precise a singular mixture of transcription elements that results in neuronal cell destiny differentiation. This SHH-induced differential gene expression creates sharp boundaries between the discrete domains of transcription issue expression, which finally patterns the ventral neural tube.[67]

The spatial and temporal side of the progressive induction of genes and cell fates within the ventral neural tube is illustrated by the expression domains of two of probably the most well-characterized transcription elements, Olig2 and Nkx2.2.[67] Early in growth, the cells on the ventral midline have solely been uncovered to a low focus of SHH for a comparatively brief time and categorical the transcription issue Olig2.[67] The expression of Olig2 quickly expands in a dorsal path concomitantly with the continual dorsal extension of the SHH gradient over time.[67] Nonetheless, because the morphogenetic entrance of SHH ligand strikes and begins to develop extra concentrated, cells which might be uncovered to greater ranges of the ligand reply by switching off Olig2 and turning on Nkx2.2,[67] creating a pointy boundary between the cells expressing the transcription issue Nkx2.2 ventral to the cells expressing Olig2. It’s on this method that every of the domains of the six progenitor cell populations are considered successively patterned all through the neural tube by the SHH focus gradient.[67] Mutual inhibition between pairs of transcription elements expressed in neighboring domains contributes to the event of sharp boundaries; nevertheless, in some instances, inhibitory relationship has been discovered even between pairs of transcription elements from extra distant domains. Significantly, NKX2-2 expressed within the V3 area is reported to inhibit IRX3 expressed in V2 and extra dorsal domains, though V3 and V2 are separated by an extra area termed MN.[70]

See Also

SHH expression within the frontonasal ectodermal zone (FEZ), which is a signaling heart that’s chargeable for the patterned growth of the higher jaw, regulates craniofacial growth mediating by means of the miR-199 household within the FEZ. Particularly, SHH-dependent indicators from the mind regulate genes of the miR-199 household with downregulations of the miR-199 genes growing SHH expression and leading to wider faces, whereas upregulations of the miR-199 genes lower SHH expression leading to slender faces.[71]

Tooth growth[edit]

SHH performs a vital function in organogenesis and, most significantly, craniofacial growth. Being that SHH is a signaling molecule, it primarily works by diffusion alongside a focus gradient, affecting cells in numerous manners. In early tooth growth, SHH is launched from the first enamel knot—a signaling heart—to offer positional data in each a lateral and planar signaling sample in tooth growth and regulation of tooth cusp development.[72] SHH specifically is required for development of epithelial cervical loops, the place the outer and inside epitheliums be part of and type a reservoir for dental stem cells. After the first enamel knots are apoptosed, the secondary enamel knots are fashioned. The secondary enamel knots secrete SHH together with different signaling molecules to thicken the oral ectoderm and start patterning the complicated shapes of the crown of a tooth throughout differentiation and mineralization.[73] In a knockout gene mannequin, absence of SHH is indicative of holoprosencephaly. Nonetheless, SHH prompts downstream molecules of Gli2 and Gli3. Mutant Gli2 and Gli3 embryos have irregular growth of incisors which might be arrested in early tooth growth in addition to small molars.[74]

Lung growth[edit]

Though SHH is mostly related to mind and limb digit growth, it’s also essential in lung growth.[75][76][77][78] Research utilizing qPCR and knockouts have demonstrated that SHH contributes to embryonic lung growth. The mammalian lung branching happens within the epithelium of the creating bronchi and lungs.[79][80] SHH expressed all through the foregut endoderm (innermost of three germ layers) within the distal epithelium, the place the embryonic lungs are creating.[77][80] This means that SHH is partially chargeable for the branching of the lungs. Additional proof of SHH’s function in lung branching has been seen with qPCR. SHH expression happens within the creating lungs round embryonic day 11 and is strongly expressed within the buds of the fetal lungs however low within the creating bronchi.[77][80] Mice who’re poor in SHH can develop tracheoesophageal fistula (irregular connection of the esophagus and trachea).[81][77] Moreover, a double (SHH-/- ) knockout mouse mannequin exhibited poor lung growth. The lungs of the SHH double knockout didn’t endure lobation and branching (i.e., the irregular lungs solely developed one department, in comparison with an extensively branched phenotype of the wildtype).[77]

Potential regenerative perform[edit]

Sonic hedgehog could play a job in mammalian hair cell regeneration. By modulating retinoblastoma protein exercise in rat cochlea, sonic hedgehog permits mature hair cells that usually can not return to a proliferative state to divide and differentiate. Retinoblastoma proteins suppress cell development by stopping cells from returning to the cell cycle, thereby stopping proliferation. Inhibiting the exercise of Rb appears to permit cells to divide. Due to this fact, sonic hedgehog—recognized as an essential regulator of Rb—may additionally show to be an essential function in regrowing hair cells after injury.[82]

SHH is essential for regulating dermal adipogenesis by hair follicle transit-amplifying cells (HF-TACs). Particularly, SHH induces dermal angiogenesis by performing immediately on adipocyte precursors and selling their proliferation by means of their expression of the peroxisome proliferator-activated receptor γ (Pparg) gene.[83]


SHH undergoes a sequence of processing steps earlier than it’s secreted from the cell. Newly synthesised SHH weighs 45 kDa and is known as the preproprotein. As a secreted protein, it accommodates a brief signal sequence at its N-terminus, which is recognised by the signal recognition particle through the translocation into the endoplasmic reticulum (ER), step one in protein secretion. As soon as translocation is full, the sign sequence is eliminated by signal peptidase within the ER. There, SHH undergoes autoprocessing to generate a 20 kDa N-terminal signaling area (SHH-N) and a 25 kDa C-terminal area with no identified signaling function.[84] The cleavage is catalysed by a protease throughout the C-terminal area. Through the response, a cholesterol molecule is added to the C-terminus of SHH-N.[85][86] Thus, the C-terminal area acts as an intein and a ldl cholesterol transferase. One other hydrophobic moiety, a palmitate, is added to the alpha-amine of N-terminal cysteine of SHH-N. This modification is required for environment friendly signaling, leading to a 30-fold enhance in efficiency over the non-palmitylated type and is carried out by a member of the membrane-bound O-acyltransferase household Protein-cysteine N-palmitoyltransferase HHAT.[87]


A possible inhibitor of the Hedgehog signaling pathway has been discovered and dubbed “Robotnikinin”—in honour of Sonic the Hedgehog’s nemesis, Dr. Ivo “Eggman” Robotnik.[88]

Former controversy surrounding identify[edit]

The gene has been linked to a situation often called holoprosencephaly, which can lead to extreme mind, cranium and facial defects, inflicting a couple of clinicians and scientists to criticize the identify on the grounds that it sounds too frivolous. It has been famous that point out of a mutation in a sonic hedgehog gene may not be effectively obtained in a dialogue of a severe dysfunction with a affected person or their household.[17][89][90] This controversy has largely died down, and the identify is now typically seen as a humorous relic of the time earlier than the rise of quick, low cost full genome sequencing and standardized nomenclature.[91] The issue of the “inappropriateness” of the names of genes comparable to “Mothers against decapentaplegic“, “Lunatic fringe“, and “Sonic hedgehog” is essentially prevented through the use of standardized abbreviations when talking with sufferers and their households.[92]


Interaction between SHH and Gli proteins which gives rise to different ventral neuronal subtypes.

SHH gradient and Gli exercise within the vertebrate neural tube.

See additionally[edit]


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