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Sonic hedgehog protein (SHH) is encoded for by the ''SHH''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. The protein is named after the character ''
Sonic the Hedgehog is a Japanese video game series and media franchise created by 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 m ...
''. 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 A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the vario ...
that patterns the developing embryo using a concentration gradient characterized by the French flag model. 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 Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed ...
, a failure of splitting in the cerebral hemispheres, 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. 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
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s including
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...
,
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...
,
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
,
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
, gallbladder and many more.


Discovery and naming

The hedgehog gene ('' hh'') was first identified in the fruit fly ''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'' in the classic Heidelberg screens of Christiane Nüsslein-Volhard and Eric Wieschaus, as published in 1980. These screens, which led to the researchers winning a
Nobel Prize The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
in 1995 along with developmental geneticist
Edward B. Lewis Edward Butts Lewis (May 20, 1918 – July 21, 2004) was an American geneticist, a corecipient of the 1995 Nobel Prize in Physiology or Medicine. He helped to found the field of evolutionary developmental biology. Early life Lewis was born in Wi ...
, identified genes that control the segmentation pattern of the ''Drosophila'' embryos. The ''hh'' loss of function mutant
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...
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. Two of these genes, ''
desert hedgehog The desert hedgehog (''Paraechinus aethiopicus'') is a species of mammal in the family Erinaceidae. Basic facts The desert hedgehog is one of the smallest of hedgehogs. It is long and weighs about . The quills (or spines to give their correct ...
'' and '' Indian hedgehog'', were named for species of hedgehogs, while ''sonic hedgehog'' was named after the video game character
Sonic the Hedgehog is a Japanese video game series and media franchise created by 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 m ...
. 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 is a Japanese video game series and media franchise created by 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 m ...
''. In the
zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
, two of the three vertebrate ''hh'' genes are duplicated: ''SHH a'' and ''SHH b'' (formerly described as ''tiggywinkle hedgehog'', named for Mrs. Tiggy-Winkle, a character from Beatrix Potter's books for children) and ''ihha'' and ''ihhb'' (formerly described as ''echidna hedgehog'', named for the spiny anteater and not for the character Knuckles the Echidna 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 A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the vario ...
involved in patterning many systems—including the
anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...
,
pallium The pallium (derived from the Roman ''pallium'' or ''palla'', a woolen cloak; : ''pallia'') is an ecclesiastical vestment in the Catholic Church, originally peculiar to the pope, but for many centuries bestowed by the Holy See upon metropol ...
of the brain,
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
,
lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...
s, teeth and the
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
by the ''
zona limitans intrathalamica The ''zona limitans intrathalamica'' (ZLI) is a lineage-restriction compartment and primary developmental boundary in the vertebrate forebrain (which is analogous to the human cerebrum) that serves as a signaling center and a restrictive border bet ...
''. In vertebrates, the development of limbs and digits depends on the secretion of sonic hedgehog by the
zone of polarizing activity The zone of polarizing activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Even ...
, located on the posterior side of the embryonic
limb bud The limb bud is a structure formed early in vertebrate limb development. As a result of interactions between the ectoderm and underlying mesoderm, formation occurs roughly around the fourth week of development. In the development of the human em ...
. Mutations in the human sonic hedgehog gene ''SHH'' cause
holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed ...
type 3 HPE3, as a result of the loss of the ventral midline. The sonic hedgehog transcription pathway has also been linked to the formation of specific kinds of cancerous tumors, including the embryonic cerebellar tumor and medulloblastoma, as well as the progression of
prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...
tumours. For SHH to be expressed in the developing embryo limbs, a morphogen called fibroblast growth factors must be secreted from the apical ectodermal ridge. Sonic hedgehog has also been shown to act as an axonal guidance cue. It has been demonstrated that SHH attracts commissural
axons An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
at the ventral midline of the developing spinal cord. Specifically, SHH attracts
retinal ganglion cell A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the ganglion cell layer) of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and reti ...
(RGC) axons at low concentrations and repels them at higher concentrations. The absence (non-expression) of SHH has been shown to control the growth of nascent hind limbs in
cetacean Cetacea (; , ) is an infraorder of aquatic mammals that includes whales, dolphins, and porpoises. Key characteristics are their fully aquatic lifestyle, streamlined body shape, often large size and exclusively carnivorous diet. They propel th ...
s (
whale Whales are a widely distributed and diverse group of fully aquatic placental marine mammals. As an informal and colloquial grouping, they correspond to large members of the infraorder Cetacea, i.e. all cetaceans apart from dolphins and ...
s and
dolphin A dolphin is an aquatic mammal within the infraorder Cetacea. Dolphin species belong to the families Delphinidae (the oceanic dolphins), Platanistidae (the Indian river dolphins), Iniidae (the New World river dolphins), Pontoporiidae (the b ...
s). The ''SHH'' gene is a member of the hedgehog gene family with five variations of DNA sequence alterations or splice variants. ''SHH'' is located on chromosome seven and initiates the production of Sonic Hedgehog protein. This protein sends short- and long-range signals to embryonic tissues to regulate development. 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. This protein functions as a vital morphogenic signaling molecule and plays an important role in the formation of many different structures in developing embryos. The ''SHH'' gene affects several major organ systems, such as the nervous system, cardiovascular system, respiratory system and musculoskeletal system. 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 Microphthalmia (Greek: grc, μικρός, mikros, small, label=none, grc, ὀφθαλμός, ophthalmos, eye, label=none, also referred as microphthalmos, is a developmental disorder of the eye in which one (unilateral microphthalmia) or both ( ...
and
Holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed ...
. Microphthalmia is a condition that affects the eyes, which results in small, underdeveloped tissues in one or both eyes. This can lead to issues ranging from a coloboma to a single small eye to the absence of eyes altogether. Holoprosencephaly is a condition most commonly caused by a mutation of the ''SHH'' gene that causes improper separation of the left and right brain and facial dysmorphia. 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.


Patterning of the central nervous system

The sonic hedgehog (SHH) signaling molecule assumes various roles in patterning the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS) during
vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with ...
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. The
notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consi ...
—a structure derived from the axial
mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Emb ...
—produces SHH, which travels extracellularly to the ventral region of the neural tube and instructs those cells to form the floor plate. Another view of 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. The neural tube itself is the initial groundwork of the vertebrate CNS, and the floor plate is a specialized structure, 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. Sonic hedgehog is the
secreted protein A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides. Secretory proteins are synthesized in the endoplasmic ret ...
that mediates signaling activities of the notochord and floor plate. Studies involving
ectopic expression Ectopic is a word used with a prefix, ecto, meaning “out of place.” Ectopic expression is an abnormal gene expression in a cell type, tissue type, or developmental stage in which the gene is not usually expressed. The term ectopic expression is ...
of SHH ''in vitro'' and ''in vivo'' result in floor plate induction and differentiation of
motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirect ...
and ventral interneurons. On the other hand, mice mutants for SHH lack ventral spinal cord characteristics. ''In vitro'' blocking of SHH signaling using
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
against it shows similar phenotypes. SHH exerts its effects in a concentration-dependent manner, so that a high concentration of SHH results in a local inhibition of
cellular proliferation Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
. 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. Once the floor plate is established, cells residing in this region will subsequently express SHH themselves, generating a
concentration gradient Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) ...
within the neural tube. Although there is no direct evidence of a SHH
gradient In vector calculus, the gradient of a scalar-valued differentiable function of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p is the "direction and rate of fastest increase". If the gr ...
, there is indirect evidence via the visualization of Patched (''Ptc'') gene expression, which encodes for the
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
binding domain of the SHH receptor throughout the ventral neural tube. ''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. 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''. Graded SHH signaling is suggested to be mediated through the
Gli Gli ( 2004 – 7 November 2020) was a Turkish European Shorthair cat from Istanbul best known for living in the Hagia Sophia, for which she became an Internet celebrity, grabbing the attention of visiting tourists. Gli was born in 2004 and w ...
family of proteins, which are vertebrate homologues of the ''Drosophila''
zinc-finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struc ...
-containing
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
'' Cubitus interruptus'' (''Ci''). ''Ci'' is a crucial mediator of hedgehog (''Hh'') signaling in ''Drosophila''. In vertebrates, three different Gli proteins are present, viz. Gli1, Gli2 and Gli3, which are expressed in the neural tube. Mice mutants for Gli1 show normal spinal cord development, suggesting that it is dispensable for mediating SHH activity. However, Gli2 mutant mice show abnormalities in the ventral spinal cord, with severe defects in the floor plate and ventral-most interneurons (V3). 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 In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
. Gli proteins have a C-terminal activation domain and an N-terminal repressive domain. 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. 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 In genealogy, the progenitor (rarer: primogenitor; german: Stammvater or ''Ahnherr'') is the – sometimes legendary – founder of a family, line of descent, clan or tribe, noble house, or ethnic group.. Ebenda''Ahnherr:''"Stammvater eines ...
domains rather than being inductive, as SHH/Gli3 mutants show intermixing of cell types. 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. Vitronectin is another protein that is induced by SHH; it acts as an obligate co-factor for SHH signaling in the neural tube. There are five distinct progenitor domains in the ventral neural tube: V3
interneuron Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. ...
s, motor neurons (MN), V2, V1, and V0 interneurons (in ventral to dorsal order). These different progenitor domains are established by "communication" between different classes of
homeobox A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full-g ...
transcription factors. (See
Trigeminal Nerve In neuroanatomy, the trigeminal nerve ( lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for sensation in the face and motor functions such as biting and che ...
.) 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. 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. 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 that ventralize the fate of the neural plate cell for a given SHH concentration. On the other hand, mutation in BMP antagonists (e.g., noggin) produces severe defects in the ventral-most characteristics of the spinal cord, followed by
ectopic expression Ectopic is a word used with a prefix, ecto, meaning “out of place.” Ectopic expression is an abnormal gene expression in a cell type, tissue type, or developmental stage in which the gene is not usually expressed. The term ectopic expression is ...
of BMP in the ventral neural tube. Interactions of SHH with Fgf and RA have not yet 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 A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the vario ...
. 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. SHH emanates from the
notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consi ...
and ventral floor plate of the developing neural tube to create a
concentration gradient Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) ...
that spans the dorso-ventral axis and is antagonized by an inverse Wnt gradient, which specifies the dorsal spinal chord. 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. 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. 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. Each of the ventral progenitor domains expresses a highly individualized combination of transcription factors—Nkx2.2, Olig2, Nkx6.1, Nkx6.2, 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. 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. 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. 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. The expression of Olig2 rapidly expands in a dorsal direction concomitantly with the continuous dorsal extension of the SHH gradient over time. 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, 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. 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. SHH expression in the frontonasal ectodermal zone (FEZ), which is a signaling center that is responsible for the patterned development of the upper jaw, regulates craniofacial development mediating through the miR-199 family in the FEZ. Specifically, SHH-dependent signals from the brain regulate genes of the miR-199 family with downregulations of the miR-199 genes increasing SHH expression and resulting in wider faces, while upregulations of the miR-199 genes decrease SHH expression resulting in narrow faces.


Tooth development

SHH plays a 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. 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. In a knockout gene model, absence of SHH is indicative of
holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed ...
. However, SHH activates downstream molecules of Gli2 and Gli3. Mutant Gli2 and Gli3 embryos have abnormal development of incisors that are arrested in early tooth development as well as small molars.


Lung development

Although SHH is most commonly associated with brain and limb digit development, it is also important in lung development. 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. SHH expressed throughout the foregut
endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...
(innermost of three germ layers) in the distal epithelium, where the embryonic lungs are developing. 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. Mice who are deficient in SHH can develop tracheoesophageal fistula (abnormal connection of the esophagus and trachea). Additionally, a double (SHH-/- ) knockout mouse model exhibited poor lung development. The lungs of the SHH double knockout failed to undergo lobation and branching (i.e., the abnormal lungs only developed one branch, compared to an extensively branched phenotype of the wildtype).


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 The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
, 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. SHH is important for regulating dermal adipogenesis by hair follicle transit-amplifying cells (HF-TACs). Specifically, SHH induces dermal angiogenesis by acting directly on adipocyte precursors and promoting their proliferation through their expression of the peroxisome proliferator-activated receptor γ (Pparg) gene.


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 The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein ( protein- RNA complex) that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma memb ...
during the translocation into the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
(ER), the first step in protein
secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...
. 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. The cleavage is catalysed by a
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
within the C-terminal domain. During the reaction, a
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
molecule is added to the C-terminus of SHH-N. Thus, the C-terminal domain acts as an intein and a cholesterol transferase. Another
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...
moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...
, a palmitate, is added to the alpha-amine of N-terminal
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...
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.


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.


Former controversy surrounding name

The gene has been linked to a condition known as
holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed ...
, 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. 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. The problem of the "inappropriateness" of the names of genes such as "
Mothers against decapentaplegic Mothers against decapentaplegic is a protein from the SMAD family that was discovered in ''Drosophila''. During ''Drosophila'' research, it was found that a mutation in the gene in the mother repressed the gene decapentaplegic in the embryo. The ...
", "Lunatic fringe", and "Sonic hedgehog" is largely avoided by using standardized abbreviations when speaking with patients and their families.


Gallery


See also

*
Pikachurin Pikachurin, also known as AGRINL (AGRINL) and EGF-like, fibronectin type-III and laminin G-like domain-containing protein (EGFLAM), is a protein that in humans is encoded by the ''EGFLAM'' gene. Pikachurin is a dystroglycan-interacting protein ...
, a retinal protein named after
Pikachu is a fictional species in the ''Pokémon'' media franchise. Designed by Atsuko Nishida and Ken Sugimori, Pikachu first appeared in the 1996 Japanese video games ''Pokémon Red'' and ''Green'' created by Game Freak and Nintendo, which w ...
* Zbtb7, an oncogene which was originally named "
Pokémon (an abbreviation for in Japan) is a Japanese media franchise managed by The Pokémon Company, founded by Nintendo, Game Freak, and Creatures, the owners of the trademark and copyright of the franchise. In terms of what each of thos ...
"


References


Further reading

* * * * * * *


External links


An introductory article on ''SHH''
at
Davidson College Davidson College is a private liberal arts college in Davidson, North Carolina. It was established in 1837 by the Concord Presbytery and named after Revolutionary War general William Lee Davidson, who was killed at the nearby Battle of Cowan� ...

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

.. New York Times November 12, 2006 ..
GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview

SHH – sonic hedgehog
US National Library of Medicine * * {{DEFAULTSORT:Sonic Hedgehog Proteins Morphogens HINT domain Cell signaling Ligands (biochemistry) Genes on human chromosome 7 Sonic the Hedgehog