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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.[6] 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,[7] 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.[8]

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.[9]

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The hedgehog gene (hh) was first identified in the fruit fly Drosophila melanogaster in the classic Heidelberg screens of Christiane Nsslein-Volhard and Eric Wieschaus, as published in 1980.[10] 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.[11][12][13][14]

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.[15][16] 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 game Sonic the Hedgehog.[17][18][19] In the zebrafish, two of the three vertebrate hh genes are duplicated: SHH a[20] and SHH b[21] (formerly described as tiggywinkle hedgehog, named for Mrs. Tiggy-Winkle, a character from Beatrix Potter's books for children) and ihha and ihhb[22] (formerly described as echidna hedgehog, named for the spiny anteater and not for the character Knuckles the Echidna in the Sonic franchise).

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.[34] Specifically, SHH attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations.[35] The absence (non-expression) of SHH has been shown to control the growth of nascent hind limbs in cetaceans[36] (whales and dolphins).

The SHH gene is a member of the hedgehog gene family with five variations of DNA sequence alterations or splice variants.[37] SHH is located on chromosome seven and initiates the production of Sonic Hedgehog protein.[37] This protein sends short- and long-range signals to embryonic tissues to regulate development.[38] 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.[39] This protein functions as a vital morphogenic signaling molecule and plays an important role in the formation of many different structures in developing embryos.[39] The SHH gene affects several major organ systems, such as the nervous system, cardiovascular system, respiratory system and musculoskeletal system.[37][38] 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.[39] Microphthalmia is a condition that affects the eyes, which results in small, underdeveloped tissues in one or both eyes.[39] This can lead to issues ranging from a coloboma to a single small eye to the absence of eyes altogether.[38] 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[40] and facial dysmorphia.[38][39] 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.

Sonic hedgehog is the secreted protein that mediates signaling activities of the notochord and floor plate.[45] Studies involving ectopic expression of SHH in vitro[46] and in vivo[47] 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.[48] In vitro blocking of SHH signaling using antibodies against it shows similar phenotypes.[47] SHH exerts its effects in a concentration-dependent manner,[49] so that a high concentration of SHH results in a local inhibition of cellular proliferation.[50] 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.[47] Once the floor plate is established, cells residing in this region will subsequently express SHH themselves,[50] 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[51] throughout the ventral neural tube.[52] 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.[53] 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.[54] 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.[55] In vertebrates, three different Gli proteins are present, viz. Gli1, Gli2 and Gli3, which are expressed in the neural tube.[56] Mice mutants for Gli1 show normal spinal cord development, suggesting that it is dispensable for mediating SHH activity.[57] However, Gli2 mutant mice show abnormalities in the ventral spinal cord, with severe defects in the floor plate and ventral-most interneurons (V3).[58] 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.[59] Gli proteins have a C-terminal activation domain and an N-terminal repressive domain.[56][60]

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.[17][90][91] 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.[92] The problem of the "inappropriateness" of the names of genes such as "Mothers against decapentaplegic", "Lunatic fringe", and "Sonic hedgehog" is largely avoided by using standardized abbreviations when speaking with patients and their families.[93]

Sonic the Hedgehog[a] is a video game series and media franchise created by the Japanese developers Yuji Naka, Naoto Ohshima, and Hirokazu Yasuhara for Sega. The franchise follows Sonic, an anthropomorphic blue hedgehog who battles the evil Doctor Eggman, a mad scientist. The main Sonic the Hedgehog games are platformers mostly developed by Sonic Team; other games, developed by various studios, include spin-offs in the racing, fighting, party and sports genres. The franchise also incorporates printed media, animations, feature films, and merchandise.

The Sonic franchise is known for its large cast of characters;[194] Sonic the Fighters (1996) producer Yu Suzuki joked that anyone who makes a Sonic game has the duty to create new characters.[195] The first game introduced Sonic, a blue hedgehog who can run at incredible speeds, and Doctor Eggman, a rotund mad scientist.[4] During the Genesis era, Eggman was referred to as Doctor Ivo Robotnik in Western territories.[196][197] Sega of America's Dean Sitton made the change[198] without consulting the Japanese developers, who did not want a single character to have two different names. Since Sonic Adventure, the character has been referred to as Eggman in all territories,[196] although the Robotnik name is still acknowledged.[197][199][200]

Much of the supporting cast was introduced in the succeeding games for the Genesis and its add-ons. Sonic 2 introduced Sonic's sidekick Miles "Tails" Prower, a fox who can fly using his two tails.[209] Sonic CD introduced Amy Rose, a pink hedgehog and Sonic's self-proclaimed girlfriend, and Metal Sonic, a robotic doppelgnger of Sonic created by Eggman.[210] Sonic 3 introduced Sonic's rival Knuckles, a red echidna and the guardian of the Master Emerald.[211] The Master Emerald, introduced in Sonic & Knuckles,[212] controls the power of the Chaos Emeralds.[202] Knuckles' Chaotix introduced the Chaotix, a group comprising Vector the Crocodile, Espio the Chameleon and Charmy Bee.[213] Three characters introduced during this period, Mighty the Armadillo and Ray the Flying Squirrel from SegaSonic the Hedgehog and Fang the Sniper from Sonic Triple Trouble (1994), faded into obscurity,[37][214] but became prominent characters again in Sonic Mania and Superstars.[215] ff782bc1db