The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-standing questions about this pathway include how the dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells and how the resistance-nodulation-division transporter Dispatched 1 (Disp, also known as Disp1) regulates this process. Here, we show that inactivation of Disp in Shh-expressing human cells impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding. We also show that cholesterol export from Disp-deficient cells is reduced, that these cells contain increased cholesterol amounts in the plasma membrane, and that Shh shedding from Disp-deficient cells is restored by pharmacological membrane cholesterol extraction and by overexpression of transgenic Disp or the structurally related protein Patched 1 (Ptc, also known as Ptch1; a putative cholesterol transporter). These data suggest that Disp can regulate Shh function via controlled cell surface shedding and that membrane cholesterol-related molecular mechanisms shared by Disp and Ptc exercise such sheddase control.
Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2(+) cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2(+) cells produce rapidly cycling doublecortin(+) progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2(+) cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2(+) cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2(+) cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2(+) cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma.
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Sonic the Hedgehog[c] is a 1991 platform game developed by Sonic Team and published by Sega for the Genesis/Mega Drive. It was released in North America on June 23 and in PAL regions and Japan the following month. Players control Sonic the Hedgehog, who can run at near supersonic speeds; Sonic sets out on a quest to defeat Dr. Robotnik, a scientist who has imprisoned animals in robots and seeks the powerful Chaos Emeralds. The gameplay involves collecting rings as a form of health, and a simple control scheme, with jumping and attacking controlled by a single button.
Development began in 1990 when Sega ordered its developers to create a game featuring a mascot for the company. The developers chose a blue hedgehog designed by Naoto Oshima after he won an internal character design contest, and named themselves Sonic Team to match their character. It uses a novel technique that allows Sonic's sprite to roll along curved scenery which was based on a concept by Oshima from 1989.[2] Sonic the Hedgehog, designed for fast gameplay, was influenced by games by Super Mario series creator Shigeru Miyamoto. The music was composed by Masato Nakamura, bassist of the J-pop band Dreams Come True.
The team developed ideas for characters, an engine, and gameplay mechanics. Development emphasized speed, so Sega considered fast creatures such as kangaroos and squirrels and eliminated designs not associated with fast animals.[3] One idea, a rabbit able to grasp objects with prehensile ears, showed promise but was too complex for the Genesis hardware. The team narrowed its search to animals that could roll into a ball, their idea for an attacking move, and considered armadillos and hedgehogs.[12] The hedgehog character, proposed by Naoto Ohshima,[15] prevailed. Ohshima went on vacation to New York, taking sketches with him. He went to Central Park and asked locals for their opinions on them, and Sonic was the favorite. A man with a moustache, who eventually became Dr. Robotnik, was in second place.[16]
Ohshima said that "Sonic" was chosen because it represented speed.[22] Ideas proposed to flesh out the character included placing him in a rock band, giving him vampire fangs, and giving him a human girlfriend named Madonna.[23] Sega of America scrapped these ideas to keep his identity simple. Sega of America also expressed concerns that most Americans would not know what a hedgehog is.[15] According to Mark Cerny, who worked in Tokyo as an intermediary between the Japanese and American Sega offices, the American staff felt the character was "unsalvageable". They made plans to educate Sonic Team on character design with the work of Will Vinton, the creator of the California Raisins.[24] They proposed a full-scale recreation of the character, but compromised with Sonic Team to simply make design changes for western audiences.[15] The antagonist was named "Dr. Eggman" in Japan and "Dr. Robotnik" in other regions as a result of a dispute between Sega's American and Japanese divisions.[18]
Sonic the Hedgehog was developed by a team of seven: two programmers, two sound engineers, and three designers,[27] although it began with just Ohshima and Naka.[22] People came onto the team as the need for content increased.[22] After being assigned a project with the code name "Defeat Mario", Ohshima and Naka began work, but encountered problems: Ohshima's Rabbit proved hard to program. Catching items and throwing them caused the action's rhythm to break. Naka stated that the rabbit was not suitable for his game engine, and he also wanted the game to be playable with only one button. Hirokazu Yasuhara came onto the team to supervise Ohshima and Naka and develop levels. He became the lead designer due to his greater experience, and found the way to make the game playable with only one button by having Sonic do damage by jumping. The trio came up with the idea of him rolling into a ball. After the hedgehog character was chosen, many characters were redrawn, and the team agreed on the environments' visual complexity, with particular focus on the colors. After this, four people came onto the team to speed development up.[28]
A growing body of evidence has underlined the existence of an intricate network of molecular mechanisms that control SHH signaling. However, how alterations of such events are involved in SHH-MB remains unclear. The signaling is triggered following the interaction of the SHH ligand with its receptor Patched (PTCH), thus relieving the repression on the co-receptor Smoothened (SMO) and leading to the activation of the GLI transcription factors (GLI1, GLI2, GLI3). GLI1 is the main downstream effector of the pathway that, by driving its own expression, provides a positive feedback loop and reinforces the signaling strength [5]. Dissecting the molecular circuitry that controls GLI1 activity is needed to unveil the mechanisms responsible for SHH-driven diseases.
Here, we show a novel mechanism of action of SALL4 in SHH-MB pathogenesis whereby its re-expression, due to loss of REN, drives the activation of GLI1. Specifically, we found that SALL4 forms a trimeric complex with GLI1 and HDAC1 to induce GLI1 protein deacetylation, thus enhancing its activity. Remarkably, inhibition of SALL4 arrests tumor growth in vitro and in vivo. These findings highlight SALL4 as a crucial player of the SHH pathway and innovative target for tailored SHH-MB therapies.
Between, saving planets, collecting Chaos Emeralds and even participating in the Olympics, there's almost nothing that Sonic can't do. In celebration of Sonic's 30th anniversary, IDW has released Sonic the Hedgehog 30th Anniversary, a collection of fun short stories highlighting the Blue Blur's many different adventures. But as one story by Justin, Travis, Griffin, and Clint McElroy explains, there is one thing left for Sonic to accomplish: getting his driver's license.
The story begins with Sonic behind the wheel, his driving instructor sitting in the passenger seat next to him. Sonic explains happily all of the perks of having a car to his instructor, Kip the Capybara. From a lack of sore feet to the ability to listen to music, the sheer number of conveniences that a car offers is enough to inspire even Sonic to get his license. The only problem is that Sonic isn't that great of a driver.
The big difference between driving in a super-charged racing machine that can transform into different vehicles on the fly and taking a casual drive through the city is that driving casually requires knowledge of traffic laws, how to be safe behind the wheel and how to brake. However, the very thought of going slow is enough to make Sonic feel a little ill. Kip asks why Sonic even wants to get his driver's license anyway if driving seems like such a hassle to him. Sonic reveals his true reason for undergoing driving lessons: chili dogs. Sonic has the chance to win a lifetime supply of chili dogs courtesy of Mr. Munch-Ums Bun-Sized Franks and the rally race he's hosting. Sonic could definitely win the race on foot, but the rules state that all contestants must drive a car.
As Sonic sinks into despair over having to learn how to drive slowly and safely, a radio broadcast reveals that the rally race is actually that very day. Although Sonic puts the pedal to the metal to try and make it on time to the race, another broadcast that the race will be postponed due to Dr. Eggman's latest attack on the city. Sonic races off to stop Dr. Eggman with Kip excited to see some real speed for once.
Watching Sonic get his driver's license is a silly and fun idea, it fits in well with the McElroys' sense of humor. Brothers Justin, Travis and Griffin McElroy and their father Clint McElroy are best known for their hit podcast My Brother, My Brother and Me and their Dungeons and Dragons-themed podcast The Adventure Zone.
While the idea of Sonic the Hedgehog learning to drive might seem like a strange concept, he has plenty of experience driving cars in all of his racing spin-off titles. His love of chili dogs goes all the way back to his original early '90s cartoons. There are even subtle references hidden in the background of the comic, too, such as how the highway signs resemble the introduction screens for the different Zones in Sonic the Hedgehog on the Sega Genesis. ff782bc1db
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