Sonic hedgehog
Encyclopedia
Sonic hedgehog homolog (SHH) is one of three protein
s in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog
(DHH) and Indian hedgehog (IHH). SHH is the best studied ligand
of the hedgehog signaling pathway. It plays a key role in regulating vertebrate
organogenesis
, such as in the growth of digits on limbs
and organization of the brain
. Sonic hedgehog is the best established example of a morphogen
as defined by Lewis Wolpert
's French flag model
—a molecule that diffuses
to form a concentration gradient and has different effects on the cells of the developing embryo
depending on its concentration. SHH remains important in the adult. It controls cell division
of adult stem cell
s and has been implicated in development of some cancers
.
, as published in 1978. These screens
, which led to their winning the Nobel Prize
in 1995 along with developmental geneticist Edward B. Lewis
, identified genes that control the segmentation pattern of Drosophila melanogaster
(fruit fly) embryo
s. The hh loss of function mutant
phenotype
causes the embryo
s to be covered with denticles (small pointy projections), resembling a hedgehog
.
Investigations aimed at finding a hedgehog equivalent in mammals revealed three homologous genes
. The first two discovered, desert hedgehog and Indian hedgehog, were named for species of hedgehog
s, while sonic hedgehog was named after Sega
's video game character Sonic the Hedgehog
. In zebrafish, the orthologues of the three mammalian hh genes are: shh a, shh b, (formerly described as tiggywinkle hedgehog named for Mrs. Tiggy-Winkle
, a character from Beatrix Potter's
books for children), and indian hedgehog b (formerly described as echidna hedgehog, named for the spiny anteater
, though this may have also been a playful reference to Knuckles the Echidna
, another character from the Sonic the Hedgehog series of video games).
involved in patterning many systems, including the limb and midline structures in the brain
, spinal cord
, the thalamus
by the zona limitans intrathalamica
and the teeth. Mutations in the human sonic hedgehog gene
, SHH, cause holoprosencephaly
type 3 (HPE3) as a result of the loss of the ventral midline. Sonic hedgehog is secreted at the zone of polarizing activity (ZPA), which is located on posterior side of a limb bud in an embryo
. The sonic hedgehog transcription pathway has also been linked to the formation of specific kinds of cancerous tumours.
More recently, sonic hedgehog has also been shown to act as an axonal guidance cue
. It has been demonstrated that Shh attracts commissural axons at the ventral midline of the developing spinal cord. Specifically, Shh attracts retinal ganglion cell
(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 cetaceans (whale
s and dolphin
s).
(CNS) during vertebrate
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
, a structure derived from the axial mesoderm
, produces Shh which travels extracellularly to the ventral region of the neural tube and instructs those cells to form 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.
Evidence for Shh as the signaling molecule emanating from the notochord comes from studies involving mutant mice. These mice, devoid of Shh signaling activity but not a notochord structure, fail to develop the floor plate. Shh exerts its effects in a concentration-dependent manner, so that a high concentration of Shh result 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. Lower concentrations 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, there is indirect evidence via the visualization of Patched expression throughout the ventral neural tube. The gradient of Shh present within the neural tube establishes several domains of interneuron
and motor neuron
progenitors as well as oligodendrocyte precursors. Evidence for the role of Shh in motor neuron induction comes from experimental depletion of Shh activity using protein interfering antibodies in vivo, resulting in the absence of differentiated motor neurons.
The different progenitor domains contained by the ventral neural tube are established by “communication” between different classes of homeobox
transcription factor
s. These transcription factors are grouped into Class I and Class II genes (depending on their response to Shh activity), and are composed of members from the Pax
, Nkx
, Dbx
, and Irx
families. Class I genes are downregulated in response to high Shh concentration (active in dorsal neural tube), and Class II genes are upregulated in response to high Shh concentration (active in ventral neural tube). Each of the two classes of transcription factors is able to repress expression of the other, a mutual antagonism that is able to create regional domains.
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 (eg. RA
, FGF
, BMP
), and complex interactions between Shh and other molecules are possible.
. 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 and ventral floor plate of the developing neural tube to create a concentration gradient that spans the dorso-ventral axis. 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, Nkx 6.2, 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. Thus, 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 domains of the six progenitor cell populations are thought to be successively patterned throughout the neural tube by the Shh concentration gradient.
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
during the translocation into the endoplasmic reticulum
(ER), the first step in protein secretion
. 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
within the C-terminal domain. During the reaction, a cholesterol
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 moiety, a palmitate
, is added to the alpha-amine of N-terminal cysteine
of SHH-N. This modification is required for efficient signaling, resulting in 30-fold increase in potency over the non-palmitylated form.
.
are told that they or their child have a mutation
in a gene such as Sonic hedgehog."
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog
DHH (hedgehog)
Desert hedgehog homolog , also known as DHH is a human gene. The protein encoded by this gene is involved in cell signaling. It is named for the Desert Hedgehog.-Function:...
(DHH) and Indian hedgehog (IHH). SHH is the best studied ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
of the hedgehog signaling pathway. It plays a key role in regulating vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
organogenesis
Organogenesis
In animal development, organogenesis is the process by which the ectoderm, endoderm, and mesoderm develop into the internal organs of the organism. Internal organs initiate development in humans within the 3rd to 8th weeks in utero...
, such as in the growth of digits on limbs
Limb (anatomy)
A limb is a jointed, or prehensile , appendage of the human or other animal body....
and organization of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. Sonic hedgehog is the best established example of a morphogen
Morphogen
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue...
as defined by Lewis Wolpert
Lewis Wolpert
Lewis Wolpert CBE FRS FRSL is a developmental biologist, author, and broadcaster.-Career:Wolpert was educated at the University of Witwatersrand , at Imperial College London, and at King's College London...
's French flag model
French flag model
The French Flag Model is a conceptual definition of a morphogen, described by Lewis Wolpert in the 1960s. A morphogen is rigorously defined as a signaling molecule that acts directly on cells to produce specific cellular responses dependent on morphogen concentration...
—a molecule that diffuses
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
to form a concentration gradient and has different effects on the cells of the developing embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
depending on its concentration. SHH remains important in the adult. It controls cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
of adult stem cell
Adult stem cell
Adult stem cells are undifferentiated cells, found throughout the body after embryonic development, that multiply by cell division to replenish dying cells and regenerate damaged tissues...
s and has been implicated in development of some cancers
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
.
Discovery
The hedgehog gene (hh) was first identified in the classic Heidelberg screens of Eric Wieschaus and Christiane Nusslein-VolhardChristiane Nüsslein-Volhard
Christiane Nüsslein-Volhard is a German biologist who won the Albert Lasker Award for Basic Medical Research in 1991 and the Nobel Prize in Physiology or Medicine in 1995, together with Eric Wieschaus and Edward B...
, as published in 1978. These screens
Genetic screen
A genetic screen is a procedure or test to identify and select individuals who possess a phenotype of interest. A genetic screen for new genes is often referred to as forward genetics as opposed to reverse genetics, the term for identifying mutant alleles in genes that are already known...
, which led to their winning the Nobel Prize
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 1995 along with developmental geneticist Edward B. Lewis
Edward B. Lewis
- External links :* *...
, identified genes that control the segmentation pattern of Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
(fruit fly) embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
s. The hh loss of function mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
causes the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
s to be covered with denticles (small pointy projections), resembling a hedgehog
Hedgehog
A hedgehog is any of the spiny mammals of the subfamily Erinaceinae and the order Erinaceomorpha. There are 17 species of hedgehog in five genera, found through parts of Europe, Asia, Africa, and New Zealand . There are no hedgehogs native to Australia, and no living species native to the Americas...
.
Investigations aimed at finding a hedgehog equivalent in mammals revealed three homologous genes
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
. The first two discovered, desert hedgehog and Indian hedgehog, were named for species of hedgehog
Hedgehog
A hedgehog is any of the spiny mammals of the subfamily Erinaceinae and the order Erinaceomorpha. There are 17 species of hedgehog in five genera, found through parts of Europe, Asia, Africa, and New Zealand . There are no hedgehogs native to Australia, and no living species native to the Americas...
s, while sonic hedgehog was named after Sega
Sega
, usually styled as SEGA, is a multinational video game software developer and an arcade software and hardware development company headquartered in Ōta, Tokyo, Japan, with various offices around the world...
's video game character Sonic the Hedgehog
Sonic the Hedgehog (character)
, trademarked Sonic The Hedgehog, is a video game character and the main protagonist of the Sonic video game series released by Sega, as well as in numerous spin-off comics, cartoons, and a feature film. The first game was released on June 23, 1991, to provide Sega with a mascot to rival Nintendo's...
. In zebrafish, the orthologues of the three mammalian hh genes are: shh a, shh b, (formerly described as tiggywinkle hedgehog named for Mrs. Tiggy-Winkle
The Tale of Mrs. Tiggy-Winkle
The Tale of Mrs. Tiggy-Winkle is a children's book written and illustrated by Beatrix Potter. It was published by Frederick Warne & Co. in October 1905. Mrs. Tiggy-winkle is a hedgehog and a washerwoman who lives in a tiny cottage in the fells of the Lake District. A child named Lucie happens upon...
, a character from Beatrix Potter's
Beatrix Potter
Helen Beatrix Potter was an English author, illustrator, natural scientist and conservationist best known for her imaginative children’s books featuring animals such as those in The Tale of Peter Rabbit which celebrated the British landscape and country life.Born into a privileged Unitarian...
books for children), and indian hedgehog b (formerly described as echidna hedgehog, named for the spiny anteater
Echidna
Echidnas , also known as spiny anteaters, belong to the family Tachyglossidae in the monotreme order of egg-laying mammals. There are four extant species, which, together with the platypus, are the only surviving members of that order and are the only extant mammals that lay eggs...
, though this may have also been a playful reference to Knuckles the Echidna
Knuckles the Echidna
Knuckles the Echidna is a video game character of the Sonic the Hedgehog game series, including spin-off games and comics. His first appearance was in Sonic the Hedgehog 3, released in 1994 to introduce a new rival for Sonic. He was presented as an antagonist who was tricked by Dr. Eggman into...
, another character from the Sonic the Hedgehog series of video games).
Function
Of the hh homologues, shh has been found to have the most critical roles in development, acting as a morphogenMorphogen
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue...
involved in patterning many systems, including the limb and midline structures in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
by the zona limitans intrathalamica
Zona limitans intrathalamica
The zona limitans intrathalamica is a lineage-restriction compartment and primary developmental boundary in the vertebrate forebrain that serves as a signaling center and a restrictive border between the thalamus and the prethalamus...
and the teeth. Mutations in the human sonic hedgehog gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, SHH, cause holoprosencephaly
Holoprosencephaly
Holoprosencephaly is a cephalic disorder in which the prosencephalon fails to develop into two hemispheres. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy...
type 3 (HPE3) as a result of the loss of the ventral midline. Sonic hedgehog is secreted at the zone of polarizing activity (ZPA), which is located on posterior side of a limb bud in an embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
. The sonic hedgehog transcription pathway has also been linked to the formation of specific kinds of cancerous tumours.
More recently, sonic hedgehog has also been shown to act as an axonal guidance cue
Axon guidance
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach the correct targets...
. It has been demonstrated that Shh attracts commissural axons at the ventral midline of the developing spinal cord. Specifically, Shh attracts retinal ganglion cell
Ganglion cell
A retinal ganglion cell is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and amacrine cells...
(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 cetaceans (whale
Whale
Whale is the common name for various marine mammals of the order Cetacea. The term whale sometimes refers to all cetaceans, but more often it excludes dolphins and porpoises, which belong to suborder Odontoceti . This suborder also includes the sperm whale, killer whale, pilot whale, and beluga...
s and dolphin
Dolphin
Dolphins are marine mammals that are closely related to whales and porpoises. There are almost forty species of dolphin in 17 genera. They vary in size from and , up to and . They are found worldwide, mostly in the shallower seas of the continental shelves, and are carnivores, mostly eating...
s).
Patterning of the central nervous system
The Sonic hedgehog (Shh) signaling molecule assumes various roles in patterning the central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) during vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
development. One of the most characterized functions of Shh is its role in the induction of the floor plate
Floor plate
The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis from the midbrain to the tail regions...
and diverse ventral cell types within the neural tube
Neural tube
In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord...
. The notochord
Notochord
The notochord is a flexible, rod-shaped body found in embryos of all chordates. It is composed of cells derived from the mesoderm and defines the primitive axis of the embryo. In some chordates, it persists throughout life as the main axial support of the body, while in most vertebrates it becomes...
, a structure derived from the axial mesoderm
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
, produces Shh which travels extracellularly to the ventral region of the neural tube and instructs those cells to form 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.
Evidence for Shh as the signaling molecule emanating from the notochord comes from studies involving mutant mice. These mice, devoid of Shh signaling activity but not a notochord structure, fail to develop the floor plate. Shh exerts its effects in a concentration-dependent manner, so that a high concentration of Shh result 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. Lower concentrations 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, there is indirect evidence via the visualization of Patched expression throughout the ventral neural tube. The gradient of Shh present within the neural tube establishes several domains of interneuron
Interneuron
An interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...
and motor neuron
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
progenitors as well as oligodendrocyte precursors. Evidence for the role of Shh in motor neuron induction comes from experimental depletion of Shh activity using protein interfering antibodies in vivo, resulting in the absence of differentiated motor neurons.
The different progenitor domains contained by the ventral neural tube are established by “communication” between different classes of homeobox
Homeobox
A homeobox is a DNA sequence found within genes that are involved in the regulation of patterns of anatomical development in animals, fungi and plants.- Discovery :...
transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. These transcription factors are grouped into Class I and Class II genes (depending on their response to Shh activity), and are composed of members from the Pax
Pax genes
Paired box genes are a family of tissue specific transcription factors containing a paired domain and usually a partial or complete homeodomain. An octapeptide may also be present...
, Nkx
NKX-homeodomain factor
NKX-homeodomain factors are a family of homeodomain transcription factors that are critical regulators of organ development.Human genes that encode NKX-homeodomain factors include:* NKX1-1, NKX1-2* NKX2-1, NKX2-2, NKX2-4, NKX2-8* NKX3-1, NKX3-2...
, Dbx
DBX1
Homeobox protein DBX1, also known as developing brain homeobox protein 1, is a protein that in humans is encoded by the DBX1 gene....
, and Irx
Iroquois homeobox factor
Iroquois homeobox factors are a family of homeodomain transcription factors that play a role in many developmental processes.Human genes that encode Iroquois homeobox factors include:* IrxA sub-group: IRX1, IRX2, IRX4* IrxB sub-group: IRX3, IRX5, IRX6...
families. Class I genes are downregulated in response to high Shh concentration (active in dorsal neural tube), and Class II genes are upregulated in response to high Shh concentration (active in ventral neural tube). Each of the two classes of transcription factors is able to repress expression of the other, a mutual antagonism that is able to create regional domains.
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 (eg. RA
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
, FGF
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
, BMP
Bone morphogenetic protein
Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...
), and complex interactions between Shh and other molecules are possible.
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 morphogenMorphogen
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue...
. 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 and ventral floor plate of the developing neural tube to create a concentration gradient that spans the dorso-ventral axis. 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, Nkx 6.2, 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. Thus, 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 domains of the six progenitor cell populations are thought to be successively patterned throughout the neural tube by the Shh concentration gradient.
Processing
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
and is referred to as the preproprotein. As a secreted protein it contains a short signal sequence
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
at its N-terminus, which is recognised by the signal recognition particle
Signal recognition particle
The signal recognition particle is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes....
during the translocation into the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER), the first step in protein secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
. Once translocation is complete, the signal sequence is removed by signal peptidase
Signal peptidase
Signal peptidases are enzymes that convert secretory and some membrane proteins to their mature form by cleaving off their N-terminal targeting signals....
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
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
within the C-terminal domain. During the reaction, a cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
molecule is added to the C-terminus of SHH-N. Thus the C-terminal domain acts as an intein
Intein
An intein is a segment of a protein that is able to excise itself and rejoin the remaining portions with a peptide bond. Inteins have also been called "protein introns"....
and a cholesterol transferase. Another hydrophobic moiety, a palmitate
Palmitic acid
Palmitic acid, or hexadecanoic acid in IUPAC nomenclature, is one of the most common saturated fatty acids found in animals and plants. Its molecular formula is CH314CO2H. As its name indicates, it is a major component of the oil from palm trees . Palmitate is a term for the salts and esters of...
, is added to the alpha-amine of N-terminal cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
of SHH-N. This modification is required for efficient signaling, resulting in 30-fold increase in potency over the non-palmitylated form.
Robotnikinin
A potential inhibitor of the Hedgehog signaling pathway has been found and dubbed 'Robotnikinin', in honor of Sonic the Hedgehog's nemesis, Dr. Ivo "Eggman" RobotnikDoctor Eggman
, also known by his alias , is a fictional video game character, the main antagonist of the Sonic the Hedgehog series created by Sega. Dr. Eggman is a rotund, mad scientist with an IQ of 300 who plans to conquer the world in order to build his Eggman Empire and is the archenemy of Sonic the Hedgehog...
.
Criticism of the name
Some clinicians and scientists criticize giving genes frivolous, whimsical, or quirky names, calling it inappropriate that patients with "a serious illness or disabilityDisability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...
are told that they or their child have a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in a gene such as Sonic hedgehog."
See also
- Zbtb7Zbtb7Zbtb7 , originally named Pokemon, is a gene that may act as a master switch for cancer, and is responsible for the proliferation of cancer throughout surrounding cells...
, a gene which was originally named "PokémonPokémonis a media franchise published and owned by the video game company Nintendo and created by Satoshi Tajiri in 1996. Originally released as a pair of interlinkable Game Boy role-playing video games developed by Game Freak, Pokémon has since become the second most successful and lucrative video...
" - PikachurinPikachurinPikachurin, also known as protein-like polysaccharide and EGF-like, fibronectin type-III and laminin G-like domain-containing polysaccharide , is a polysaccharide that in humans is encoded by the EGFLAM gene...
, a retinal protein named after PikachuPikachuis one of the species of Pokémon creatures from the Pokémon media franchise—a collection of video games, anime, manga, books, trading cards, and other media created by Satoshi Tajiri. As do all Pokémon, Pikachu fight other Pokémon in battles central to the anime, manga, and games of the series...
External links
- An introductory article on shh at Davidson CollegeDavidson CollegeDavidson College is a private liberal arts college in Davidson, North Carolina. The college has graduated 23 Rhodes Scholars and is consistently ranked in the top ten liberal arts colleges in the country by U.S. News and World Report magazine, although it has recently dropped to 11th in U.S. News...
- http://www.gdb.org/gdb-bin/genera/genera/hgd/GenomicSegment?!action=query&displayName=shhSHH at The GDB Human Genome DatabaseGDB Human Genome DatabaseThe GDB Human Genome Database was a community curated collection of human genomic data. What set GDB apart from other biological databases was its use of world-class leaders in human genetics to act as curators for the data. In order to ensure a high degree of quality, records within GDB were...
] - 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
- ‘Sonic Hedgehog’ sounded funny, at first. New York Times, November 12, 2006.
- GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview