Sonic Hedgehog (protein)
   HOME

TheInfoList



OR:

Sonic hedgehog protein (SHH) is a major
signaling molecule In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...
of embryonic development in humans and animals, encoded by the ''SHH''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls
organogenesis Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...
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 The French flag model is a conceptual definition of a morphogen, described by Lewis Wolpert in the 1960s. A morphogen is defined as a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular resp ...
. 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 Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...
, 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 Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s including
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
,
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 The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
,
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath t ...
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 (an insect of the Order (biology), 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", "pomace fly" ...
'' in the classic Heidelberg screens of Christiane Nüsslein-Volhard and
Eric Wieschaus Eric Francis Wieschaus (born June 8, 1947 in South Bend, Indiana) is an American Evolutionary developmental biology, evolutionary developmental biologist and 1995 Nobel Prize-winner. Early life Born in South Bend, Indiana, he attended John Carro ...
, as published in 1980. These screens, which led to the researchers winning a
Nobel Prize The Nobel Prizes ( ; ; ) are awards administered by the Nobel Foundation and granted in accordance with the principle of "for the greatest benefit to humankind". The prizes were first awarded in 1901, marking the fifth anniversary of Alfred N ...
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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
causes the embryos to be covered with denticles, i.e. small pointy projections resembling the spikes of a
hedgehog A hedgehog is a spiny mammal of the subfamily Erinaceinae, in the eulipotyphlan family Erinaceidae. There are 17 species of hedgehog in five genera found throughout parts of Europe, Asia, and Africa, and in New Zealand by introduction. The ...
. 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'' and ''
Indian hedgehog The Indian hedgehog (''Paraechinus micropus'') is a species of hedgehog native to India and Pakistan. It mainly lives in sandy desert areas but can be found in other environments. Description The Indian hedgehog can be compared to the long-eare ...
'', were named for species of hedgehogs, while ''sonic hedgehog'' was named after the video game character
Sonic the Hedgehog 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 the Hedgehog (character), Sonic, an anthropomorphic blue hedgehog who battle ...
. 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 first game in the series, ''
Sonic the Hedgehog 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 the Hedgehog (character), Sonic, an anthropomorphic blue hedgehog who battle ...
'' (1991). In the zebrafish, 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 involved in patterning many systems—including the
anterior pituitary The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...
,
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 metropolitan bish ...
of the brain,
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
,
lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
s, teeth and the
thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
by the '' zona limitans intrathalamica''. In vertebrates, the
development Development or developing may refer to: Arts *Development (music), the process by which thematic material is reshaped * Photographic development *Filmmaking, development phase, including finance and budgeting * Development hell, when a proje ...
of limbs and digits depends on the secretion of sonic hedgehog by the zone of polarizing activity, 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 human embryonic development, the ...
. 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 Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...
type 3 HPE3, as a result of the loss of the
ventral Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...
midline. The sonic hedgehog transcription pathway has also been linked to the formation of specific kinds of cancerous tumors, including the embryonic
cerebellar The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or e ...
tumor and medulloblastoma, as well as the progression of
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
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 pot ...
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 photoreceptor cell, photoreceptors via two intermediate neuron types: Bipolar ...
(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 belonging to the order Artiodactyla that includes whales, dolphins and porpoises. Key characteristics are their fully aquatic lifestyle, streamlined body shape, often large size and exclusively c ...
s (
whale Whales are a widely distributed and diverse group of fully Aquatic animal, aquatic placental mammal, placental marine mammals. As an informal and Colloquialism, colloquial grouping, they correspond to large members of the infraorder Cetacea ...
s and
dolphin A dolphin is an aquatic mammal in the cetacean clade Odontoceti (toothed whale). Dolphins belong to the families Delphinidae (the oceanic dolphins), Platanistidae (the Indian river dolphins), Iniidae (the New World river dolphins), Pontopori ...
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 and
Holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...
. 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 or turn 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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS) during
vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...
development Development or developing may refer to: Arts *Development (music), the process by which thematic material is reshaped * Photographic development *Filmmaking, development phase, including finance and budgeting * Development hell, when a proje ...
. 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 In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...
. The
notochord The notochord is an elastic, rod-like structure found in chordates. In vertebrates the notochord is an embryonic structure that disintegrates, as the vertebrae develop, to become the nucleus pulposus in the intervertebral discs of the verteb ...
—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 ...
—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 In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...
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 that mediates signaling activities of the notochord and floor plate. Studies involving ectopic expression of SHH ''in vitro'' and ''in vivo'' result in floor plate induction and differentiation of
motor neuron A motor neuron (or motoneuron), also known as 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 o ...
and ventral
interneurons Interneurons (also called internuncial neurons, association neurons, connector neurons, or intermediate neurons) are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, ena ...
. On the other hand, mice mutants for SHH lack ventral spinal cord characteristics. ''In vitro'' blocking of SHH signaling using
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
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. This inhibition causes the floor plate to become thin compared to the lateral regions of the
neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...
. 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 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 f of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p gives the direction and the rate of fastest increase. The g ...
, 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 with a 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 el ...
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 family of proteins, which are vertebrate homologues of the ''Drosophila'' zinc-finger-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 (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
'' 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 i ...
. 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, a progenitor (rarer: primogenitor; or ''Ahnherr'') is the founder (sometimes one that is legendary) of a family, line of descent, gens, clan, tribe, noble house, or ethnic group.. Ebenda''Ahnherr:''"Stammvater eines Geschlec ...
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 Vitronectin (VTN or VN) is a glycoprotein of the hemopexin family which is synthesized and excreted by the liver, and abundantly found in serum, the extracellular matrix and bone. In humans it is encoded by the ''VTN'' gene. Vitronectin bind ...
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, association neurons, connector neurons, or intermediate neurons) are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, enab ...
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 Nucleic acid sequence, DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of ...
transcription factors. (See
Trigeminal Nerve In neuroanatomy, the trigeminal nerve (literal translation, lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for Sense, sensation in the face and motor functions ...
.) 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 dbx or DBX may refer to: * dbx (debugger), a Unix source-level debugger * dbx (company), a professional audio recording equipment company ** dbx (noise reduction), a noise reduction system invented by dbx, Inc. * .dbx, the file extension for Micros ...
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 In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...
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 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 Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...
neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...
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 A motor neuron (or motoneuron), also known as 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 ...
. SHH emanates from the
notochord The notochord is an elastic, rod-like structure found in chordates. In vertebrates the notochord is an embryonic structure that disintegrates, as the vertebrae develop, to become the nucleus pulposus in the intervertebral discs of the verteb ...
and ventral floor plate of the developing 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 cord. 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 A progenitor cell is a Cell (biology), biological cell that can Cellular differentiation, differentiate into a specific cell type. Stem cell, Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than ...
. 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 an 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 Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...
. 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 gastr ...
(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 Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...
activity in rat cochlea, sonic hedgehog allows mature hair cells that normally cannot return to a proliferative state to divide and differentiate.
Retinoblastoma protein Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...
s suppress cell growth by preventing cells from returning to the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
, 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 membrane ...
during the translocation into the
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
(ER), the first step in protein
secretion 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 classical mec ...
. Once translocation is complete, the signal sequence is removed by
signal peptidase Signal peptidases are enzymes that convert secretory and some membrane proteins to their mature or pro forms by cleaving their signal peptides from their N-termini. Signal peptidases were initially observed in endoplasmic reticulum (ER)-deri ...
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 catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
within the C-terminal domain. During the reaction, a
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
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 chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
moiety, 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 chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
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"—after Sonic the Hedgehog's nemesis and the main antagonist of the Sonic the Hedgehog game series, 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 Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...
, 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," " Lunatic fringe," and "Sonic hedgehog" is largely avoided by using standardized abbreviations when speaking with patients and their families.


Summary

Sonic Hedgehog (SHH) is a signaling molecule that helps shape the spinal cord in early embryonic development. It establishes cell types based on a top-to-bottom pattern. In CNS development, SHH functions as a morphogen in the early stages of vertebrate ventral neural-tube development. Dorsoventral differentiation of neural tube cells is attributed to the secretion of SHH by the notochord. This secretion of SHH is what induces the differentiation of the floor plate. Another theory suggests that each of the notochord, floor plate, and endoderm can secrete SHH because of their shared origin in the Hensen's Node. In vertebrates, such as mice, the Gli2 gene contributes greatly to expressing the SHH signaling pathway. Mice lacking the Gli2 gene show similar developmental defects to mice that are lacking the SHH gene. These defects include missing vertebrae and spinal disks. Since these two genes, when lacking, express similar defects, it is thought that the Gli gene is the primary transducer of SHH signaling. Fisher CE, Howie SEM, eds. Shh and Gli signalling and development. 1st ed. Springer; 2006:5-6. doi:10.1007/978-0-387-39957-7


Gallery

File:Shh and Gli proteins interactions.svg, alt=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, Concentration gradient of SHH


See also

* Pikachurin, a retinal protein named after Pikachu * Zbtb7, an oncogene which was originally named "
Pokémon is a Japanese media franchise consisting of List of Pokémon video games, video games, Pokémon (TV series), animated series and List of Pokémon films, films, Pokémon Trading Card Game, a trading card game, and other related media. The fran ...
"


References


Further reading

* * * * * * *


External links


An introductory article on ''SHH''
at
Davidson College Davidson College is a Private college, private Liberal arts colleges in the United States, liberal arts college in Davidson, North Carolina, United States. It was established in 1837 by the Concord Presbytery and named after American Revolutiona ...

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