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The Hedgehog signaling pathway is a
signaling pathway In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
that transmits information to
embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
nic cells required for proper
cell differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include
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 ...
. The Hedgehog signaling pathway is one of the key regulators of animal development and is present in all
bilateria The Bilateria or bilaterians are animals with bilateral symmetry as an embryo, i.e. having a left and a right side that are mirror images of each other. This also means they have a head and a tail (anterior-posterior axis) as well as a belly and ...
ns. The pathway takes its name from its
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
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 electr ...
, an intracellular signaling molecule called Hedgehog (''Hh'') found in fruit flies of the genus ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
''; fruit fly larva lacking the ''Hh'' gene are said to resemble
hedgehog A hedgehog is a spiny mammal of the subfamily Erinaceinae, in the eulipotyphlan family Erinaceidae. There are seventeen species of hedgehog in five genera found throughout parts of Europe, Asia, and Africa, and in New Zealand by introducti ...
s. ''Hh'' is one of Drosophila's
segment polarity gene A segmentation gene is a generic term for a gene whose function is to specify tissue pattern in each repeated unit of a segmented organism. Animals are constructed of segments; however, Drosophila segments also contain subdivided compartments. The ...
products, involved in establishing the basis of the fly
body plan A body plan, ( ), or ground plan is a set of morphological features common to many members of a phylum of animals. The vertebrates share one body plan, while invertebrates have many. This term, usually applied to animals, envisages a "blueprin ...
. Larvae without ''Hh'' are short and spiny, resembling the hedgehog animal. The molecule remains important during later stages of
embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
and
metamorphosis Metamorphosis is a biological process by which an animal physically develops including birth or hatching, involving a conspicuous and relatively abrupt change in the animal's body structure through cell growth and differentiation. Some inse ...
. Mammals have three Hedgehog homologues, Desert (DHH), Indian (IHH), and Sonic (SHH), of which Sonic is the best studied. The pathway is equally important during vertebrate embryonic development and is therefore of interest in
evolutionary developmental biology Evolutionary developmental biology (informally, evo-devo) is a field of biological research that compares the developmental processes of different organisms to infer how developmental processes evolved. The field grew from 19th-century beginni ...
. In
knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
lacking components of the pathway, the
brain A brain is an 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 vision. It is the most complex organ in a v ...
,
skeleton A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...
,
musculature Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
,
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
and
lungs 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 th ...
fail to develop correctly. Recent studies point to the role of Hedgehog signaling in regulating
adult stem cell Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek σωματικóς, ...
s involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some
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. Drugs that specifically target Hedgehog signaling to fight this disease are being actively developed by a number of
pharmaceutical companies The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate symptoms. ...
.


Discovery

In the 1970s, a fundamental problem in
developmental biology Developmental biology is the study of the process by which animals and plants grow and develop. Developmental biology also encompasses the biology of Regeneration (biology), regeneration, asexual reproduction, metamorphosis, and the growth and di ...
was to understand how a relatively simple egg can give rise to a complex segmented body plan. In the late 1970s
Christiane Nüsslein-Volhard Christiane (Janni) Nüsslein-Volhard (; born 20 October 1942) is a German developmental biologist and a 1995 Nobel Prize in Physiology or Medicine laureate. She is the only woman from Germany to have received a Nobel Prize in the sciences. Nü ...
and
Eric Wieschaus Eric Francis Wieschaus (born June 8, 1947 in South Bend, Indiana) is an American evolutionary developmental biologist and 1995 Nobel Prize-winner. Early life Born in South Bend, Indiana, he attended John Carroll Catholic High School in Birming ...
isolated mutations in genes that control development of the segmented anterior-posterior body axis of the fly; their "saturation mutagenesis" technique resulted in the discovery of a group of genes involved in the development of body segmentation, helping to found the field of
evolutionary developmental biology Evolutionary developmental biology (informally, evo-devo) is a field of biological research that compares the developmental processes of different organisms to infer how developmental processes evolved. The field grew from 19th-century beginni ...
. In 1995, they shared the
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 ...
with
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 ...
for their work studying genetic mutations in ''Drosophila'' embryogenesis.1995 Nobel Prize for discovery o
the genetic control of early embryonic development
/ref> The ''Drosophila'' hedgehog (''hh'') gene was identified as one of several genes important for creating the differences between the anterior and posterior parts of individual body segments. The fly ''hh'' gene was independently cloned in 1992 by the labs of Jym Mohler, Philip Beachy, Thomas B. Kornberg and Saigo Kaoru. Some hedgehog mutants result in abnormally-shaped embryos that are unusually short and stubby compared to
wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
embryos. The function of the hedgehog segment polarity gene has been studied in terms of its influence on the normally polarized distribution of larval cuticular denticles as well as features on adult appendages such as legs and antennae. Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). The appearance of the stubby and "hairy" larvae inspired the name '
hedgehog A hedgehog is a spiny mammal of the subfamily Erinaceinae, in the eulipotyphlan family Erinaceidae. There are seventeen species of hedgehog in five genera found throughout parts of Europe, Asia, and Africa, and in New Zealand by introducti ...
'.


Fruit fly


Mechanism

Insect cells express a full size
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 ...
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 fu ...
Cubitus interruptus Ci protein, short for Cubitus interruptus, is a zinc finger containing transcription factor involved in the Hedgehog signaling pathway. In the absence of a signal to the Hedgehog signaling pathway, the Ci protein is cleaved and destroyed in protea ...
(Ci), which forms a complex with the
kinesin A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule (MT) filaments and are powered by the hydrolysis of adenosine triphosphate (ATP) (thus kinesins are ATPases, a type of enzy ...
-like protein Costal-2 (Cos2) and is localized in the cytoplasm bound to cellular
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
s (Figure 2). The
SCF complex Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has impo ...
targets the 155 kDa full length Ci protein for
proteosome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...
-dependent cleavage, which generates a 75 kDa fragment (CiR). CiR builds up in the cell and diffuses into the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...
, where it acts as a co-
repressor In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
for Hedgehog (''Hh'') target genes. The steps leading to Ci protein
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
include
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of Ci protein by several
protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s; PKA,
GSK3β Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...
and CK1 (Figure 2). The ''Drosophila'' protein Slimb is part of an
SCF complex Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has impo ...
that targets proteins for
ubiquitylation Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fou ...
. Slimb binds to
phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
Ci protein. In the absence of Hh (Figure 3), a cell-surface transmembrane protein called
Patched Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segme ...
(PTCH) acts to prevent high expression and activity of a 7 membrane spanning receptor called
Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
(SMO). Patched has sequence similarity to known membrane transport proteins. When extracellular Hh is present (Figure 3), it binds to and inhibits Patched, allowing Smoothened to accumulate and inhibit the proteolytic cleavage of the Ci protein. This process most likely involves the direct interaction of Smoothened and Costal-2 and may involve sequestration of the Ci protein-containing complex to a microdomain where the steps leading to Ci protein proteolysis are disrupted. The mechanism by which Hh binding to Patched leads to increased levels of Smoothened is not clear (Step 1 in Figure 3). Following binding of Hh to Patched, Smoothened levels increase greatly over the level maintained in cells when Patched is not bound to Hh. It has been suggested that phosphorylation of Smoothened plays a role in Hh-dependent regulation of Smoothened levels. In cells with Hh-activated Patched (Figure 3), the intact Ci protein accumulates in the cell cytoplasm and levels of CiR decrease, allowing transcription of some genes such as
decapentaplegic Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly ''Drosophila melanogaster'' and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early ' ...
(dpp, a member of the BMP growth factor family). For other Hh-regulated genes, expression requires not only the loss of CiR but also the positive action of uncleaved Ci to act as a
transcriptional activator A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and, ...
. Costal-2 is normally important for holding Ci protein in the cytoplasm, but interaction of Smoothened with Costal-2 allows some intact Ci protein to go to the nucleus. The ''Drosophila'' protein Fused (Fu in Figure 3) is a protein kinase that binds to Costal-2. Fused can inhibit Suppressor of Fused (SUFU), which in turn interacts with Ci to regulate gene transcription in some cell types.


Role

Hedgehog has roles in larval body segment development and in formation of adult appendages. During the formation of body segments in the developing ''Drosophila'' embryo, stripes of cells that synthesize the
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 fu ...
engrailed can also express the cell-to-cell signaling protein Hedgehog (green in Figure 4). Hedgehog is not free to move very far from the cells that make it and so it only activates a thin stripe of cells adjacent to the engrailed-expressing cells. When acting in this local fashion, hedgehog works as a
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
factor. Only cells to one side of the engrailed-expressing cells are competent to respond to Hedgehog following interaction of Hh with the receptor protein Patched (blue in Figure 4). Cells with Hh-activated Patched receptor synthesize the
Wingless The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
protein (red in Figure 4). If a ''Drosophila'' embryo is altered so as to produce Hh in all cells, all of the competent cells respond and form a broader band of Wingless-expressing cells in each segment. The ''wingless'' gene has an upstream transcription regulatory region that binds the Ci transcription factor in a Hh-dependent fashion resulting in an increase in ''wingless'' transcription (interaction 2 in Figure 3) in a stripe of cells adjacent to the stripe of Hh-producing cells. Wingless protein acts as an extracellular signal and patterns the adjacent rows of cells by activating its cell surface receptor
Frizzled Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol. Species distribution Fr ...
. Wingless acts on engrailed-expressing cells to stabilize the stripes of engrailed expression. Wingless is a member of the Wnt family of cell-to-cell signaling proteins. The reciprocal signaling by Hedgehog and Wingless stabilizes the boundary between parasegments (Figure 4, top). The effects of Wingless and Hedgehog on other stripes of cells in each segment establishes a positional code that accounts for the distinct anatomical features along the anterior-posterior axis of the segments. The Wingless protein is called "wingless" because of the
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
of some ''wingless'' fly mutants. Wingless and Hedgehog function together during
metamorphosis Metamorphosis is a biological process by which an animal physically develops including birth or hatching, involving a conspicuous and relatively abrupt change in the animal's body structure through cell growth and differentiation. Some inse ...
to coordinate wing formation. Hedgehog is expressed in the posterior part of developing ''Drosophila'' limbs. Hedgehog also participates in the coordination of eye, brain, gonad, gut and tracheal development. Downregulation of hedgehog has been implicated in reduced eye development in the amphipod '' Gammarus minus''.


Annelids

''Hedgehog'' is also involved in segmentation in the annelid worms; because
parallel evolution Parallel evolution is the similar development of a trait in distinct species that are not closely related, but share a similar original trait in response to similar evolutionary pressure.Zhang, J. and Kumar, S. 1997Detection of convergent and paral ...
seems unlikely, this suggests a common origin of segmentation between the two phyla. Whilst Hh does not induce the formation of segments, it seems to act to stabilize the segmented fields once they have appeared.


Vertebrates


Mechanism

Sonic hedgehog (SHH) is the best studied ligand of the vertebrate pathway. Most of what is known about hedgehog signaling has been established by studying SHH. It is
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
as a ~45kDa precursor and undergoes
autocatalytic A single chemical reaction is said to be autocatalytic if one of the reaction products is also a catalyst for the same or a coupled reaction.Steinfeld J.I., Francisco J.S. and Hase W.L. ''Chemical Kinetics and Dynamics'' (2nd ed., Prentice-Hall 199 ...
processing (Process "1" on Figure 5) to produce an ~20kDa
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
signaling domain (referred to as SHH-N) and a ~25kDa
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
domain with no known signaling role. During the cleavage, 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 mem ...
molecule is added to the
carboxyl In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
end of the N-terminal domain, which is involved in trafficking, secretion and receptor interaction of the ligand. SHH can signal in an
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...
fashion, affecting the cells in which it is produced.
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 classical ...
and consequent
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
hedgehog signaling require the participation of Dispatched (DISP) protein (Process "2" on Figure 5). When SHH reaches its target cell, it binds to the Patched-1 (PTCH1) receptor (Process "3" on Figure 5, the blue molecule). In the absence of ligand, PTCH1 inhibits
Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
(SMO), a downstream protein in the pathway (Process "4"). It has been suggested that SMO is regulated by a small molecule, the cellular localization of which is controlled by PTCH.
PTCH1 Protein patched homolog 1 is a protein that is the member of the patched family and in humans is encoded by the ''PTCH1'' gene. Function PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule ...
has
homology Homology may refer to: Sciences Biology *Homology (biology), any characteristic of biological organisms that is derived from a common ancestor * Sequence homology, biological homology between DNA, RNA, or protein sequences *Homologous chrom ...
to Niemann-Pick disease, type C1 (
NPC1 Niemann-Pick disease, type C1 (NPC1) is a disease of a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the ''NPC1'' gene (chromosome location 18q11). Function NPC1 was identi ...
) that is known to transport
lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...
molecules across a membrane. PTCH1 has a
sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the go ...
sensing domain (SSD), which has been shown to be essential for suppression of SMO activity. A current theory suggests that PTCH regulates SMO by removing oxysterols from SMO. PTCH acts like a sterol pump and removes oxysterols that have been created by 7-dehydrocholesterol reductase. Upon binding of a Hh protein or a mutation in the SSD of PTCH, the pump is turned off allowing oxysterols to accumulate around SMO. This accumulation of sterols allows SMO to become active or stay on the membrane for a longer period of time. This hypothesis is supported by the existence of a number of small molecule
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s and
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
s of the pathway that act on SMO. The binding of SHH relieves SMO inhibition, leading to activation of the GLI
transcription factors 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 func ...
(Process "5"): the activators
Gli1 Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells. Function The Gli proteins are the effectors of Hedgehog (Hh) ...
and Gli2 and the
repressor In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
Gli3 Zinc finger protein GLI3 is a protein that in humans is encoded by the ''GLI3'' gene. This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription f ...
. The sequence of molecular events that connect SMO to GLIs is poorly understood. Activated GLI accumulates in the nucleus (Process "6") and controls the transcription of hedgehog target genes (Process "7"). PTCH1 has recently been reported to repress transcription of hedgehog target genes through a mechanism independent of
Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
. In addition to PTCH1, mammals have another hedgehog receptor, PTCH2, whose
sequence identity In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Ali ...
with PTCH1 is 54%. All three mammalian hedgehogs bind both receptors with similar
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...
, so PTCH1 and PTCH2 cannot discriminate between the ligands. They do, however, differ in their expression patterns. PTCH2 is expressed at much higher levels in the
testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
and mediates desert hedgehog signaling there. It appears to have a distinct downstream signaling role from PTCH1. In the absence of
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 electr ...
binding PTCH2 has a decreased ability to inhibit the activity of SMO. Furthermore, overexpression of PTCH2 does not replace mutated PTCH1 in
basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
. In invertebrates, just as in ''Drosophila'', the binding of Hedgehog to PTCH leads to
internalisation Internalization ( or internalisation) is the process of making something internal, with more specific meanings in various fields. It is the opposite of externalization. Psychology and sociology In psychology, internalization is the outcome of ...
and sequestration of the ligand. Consequently, ''in vivo'' the passage of hedgehog over a receptive field that expresses the receptor leads to attenuation of the signal, an effect called ligand-dependent antagonism (LDA). In contrast to ''Drosophila'', vertebrates possess another level of hedgehog regulation through LDA mediated by Hh-interacting protein 1 (HHIP1). HHIP1 also sequesters hedgehog ligands, but unlike PTCH, it has no effect on the activity of SMO.


Role

Members of the hedgehog family play key roles in a wide variety of developmental processes. One of the best studied examples is the action of Sonic hedgehog during development of the vertebrate limb. The classic experiments of Saunders and Gasseling in 1968 on the development of the chick limb bud formed the basis of the
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 various ...
concept. They showed that identity of the digits in the chick limb was determined by a diffusible factor produced 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. Ev ...
(ZPA), a small region of tissue at the posterior margin of the limb. Mammalian development appeared to follow the same pattern. This diffusible factor was later shown to be Sonic hedgehog. However, precisely how SHH determines digit identity remained elusive until recently. The current model, proposed by Harfe ''et al.'', states that both the concentration and the time of exposure to SHH determines which digit the tissue will develop into in the
mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
(figure 6). Digits V, IV and part of III arise directly from cells that express SHH during
embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
. In these cells SHH signals in an
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...
fashion and these digits develop correctly in the absence of DISP, which is required for extracellular diffusion of the ligand. These digits differ in the length of time that SHH continues to be expressed. The most posterior digit V develops from cells that express the ligand for the longest period of time. Digit IV cells express SHH for a shorter time, and digit III cells shorter still. Digit II develops from cells that are exposed to moderate concentrations of extracellular SHH. Finally, Digit I development does not require SHH. It is, in a sense, the default program of limb bud cells. Hedgehog signaling remains important in the adult. Sonic hedgehog has been shown to promote the proliferation of
adult stem cell Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek σωματικóς, ...
s from various tissues, including primitive
hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
cells, mammary and neural stem cells. Activation of the hedgehog pathway is required for transition of the
hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...
from the resting to the growth phase. This failed due to toxicities found in animal models.


Human disease

Disruption of hedgehog signaling during embryonic development, through either deleterious mutation or consumption of teratogens by the gestating mother, can lead to severe developmental abnormalities.
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 and t ...
, the failure of the embryonic
prosencephalon In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the Anatomical terms of location#Directional terms, rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hin ...
to divide to form cerebral hemispheres, occurs with a frequency of about 1 in 8,000 live births and about 1 in 200 spontaneous abortions in humans and is commonly linked to mutations in genes involved in the hedgehog pathway, including ''SHH'' and ''PTCH''.
Cyclopia Cyclopia (named after the Greek mythology character cyclopes) is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of ...
, one of the most severe defects 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 and t ...
, results if the pathway inhibitor
cyclopamine Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily ('' Veratrum californicum'') that causes fatal birth defects. It prevents the embryo ...
is consumed by gestating mammals. Activation of the hedgehog pathway has been implicated in the development 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 in various organs, including
brain A brain is an 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 vision. It is the most complex organ in a v ...
,
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 t ...
,
mammary gland A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in primat ...
,
prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
and
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 cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
.
Basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
, the most common form of cancerous
malignancy Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
, has the closest association with hedgehog signaling. Loss-of-function mutations in
Patched Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segme ...
and activating mutations in
Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
have been identified in patients with this disease. Abnormal activation of the pathway probably leads to development of disease through transformation of
adult stem cell Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek σωματικóς, ...
s into
cancer stem cell Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. ...
s that give rise to the tumor. Cancer researchers hope that specific inhibitors of hedgehog signaling will provide an efficient therapy for a wide range of malignancies. The connection between the hedgehog signaling pathway and cancer development is very complex. Nevertheless, it is clear that the aberrant activation of hedgehog signaling leads to the growth, proliferation, and invasion of tumor cells. Besides its involvement in the development 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, hedgehog pathway may also contribute to major respiratory diseases such as pulmonary
fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
. and
chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
.


Targeting the hedgehog pathway

The most common way to target this pathway is modulate SMO.
Antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
and
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of SMO have already shown to affect the pathway regulation downstream. Several hedgehog signaling pathway inhibitors are available for cancer treatment, such as vismodegib and sonidegib. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers. SMO inhibitors represent a potential treatment for some types of cancers. However, because of harmful and potentially toxic side-effects of SMO inhibitors, undetermined safety in children, and the evidence that some patients develop resistance to SMO inhibitors, new classes of drugs are needed. The most clinically advanced SMO targeting agents are
cyclopamine Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily ('' Veratrum californicum'') that causes fatal birth defects. It prevents the embryo ...
-competitive.
Itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth ...
( Sporanox) has also been shown to target SMO through a mechanism distinct from
cyclopamine Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily ('' Veratrum californicum'') that causes fatal birth defects. It prevents the embryo ...
and
vismodegib Vismodegib (trade name Erivedge ) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administrati ...
. Itraconazole (ITZ) inhibits SMO in the presence of mutations conferring resistance to
vismodegib Vismodegib (trade name Erivedge ) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administrati ...
and other
cyclopamine Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily ('' Veratrum californicum'') that causes fatal birth defects. It prevents the embryo ...
-competitive antagonists, like IPI-926 and Novartis' LDE-225. PTCH and Gli3 (5E1) antibodies are also a way to regulate the pathway. A downstream effector and strong transcriptional activator siRNA Gli1 has been used to inhibit cell growth and promote apoptosis.
Arsenic trioxide Arsenic trioxide, sold under the brand name Trisenox among others, is an inorganic compound and medication. As an industrial chemical, whose major uses include in the manufacture of wood preservatives, pesticides, and glass. As a medication, i ...
(
Trisenox Arsenic trioxide, sold under the brand name Trisenox among others, is an inorganic compound and medication. As an industrial chemical, whose major uses include in the manufacture of wood preservatives, pesticides, and glass. As a medication, it ...
) has also been shown to inhibit hedgehog signaling by interfering with Gli function and transcription. Several environmental modifiers of Hedgehog signaling have been identified, which are potential health or developmental hazards. Dietary alkaloids found in tomatoes (tomatodine), potatoes (solanidine), nightshades like peppers and eggplant (solasodine). and turmeric (curcumin) have been shown to antagonize SMO and perturb Hedgehog signaling. In addition, certain environmental toxicants can block Hedgehog signaling.
Piperonyl butoxide Piperonyl butoxide (PBO) is a pale yellow to light brown liquidNational Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Tr ...
(PBO) is a semisynthetic pesticide additive developed in the 1940s, which can be found in thousands of household and agricultural products. Despite its widespread use, the ability of PBO to inhibit hedgehog signaling and act as a potent developmental teratogen was not recognized until recently.


Metastasis

Activation of the Hedgehog pathway leads to an increase in Snail protein expression and a decrease in
E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian ...
and
tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...
s.


Tumor regulation

Activation of the Hedgehog pathway leads to an increase in Angiogenic Factors (angiopoietin-1 and angiopoietin-2), Cyclins (cyclin D1 and B1), anti-apoptotic genes and a decrease in apoptotic genes (Fas).


Clinical trials

*
Vismodegib Vismodegib (trade name Erivedge ) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administrati ...
FDA approved (Jan 2012) for
basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
. *
Sonidegib Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer. Sonidegib is Hedgehog signaling pathway inhibitor (via smoothened antagonism). Approvals and indications It was approved for medical use in the United State ...
FDA approved (July 2015) for
basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
. *
Itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth ...


Evolution

Lancelet The lancelets ( or ), also known as amphioxi (singular: amphioxus ), consist of some 30 to 35 species of "fish-like" benthic filter feeding chordates in the order Amphioxiformes. They are the modern representatives of the subphylum Cephalochorda ...
s, which are primitive
chordate A chordate () is an animal of the phylum Chordata (). All chordates possess, at some point during their larval or adult stages, five synapomorphies, or primary physical characteristics, that distinguish them from all the other taxa. These fiv ...
s, possess only one homologue of ''Drosophila'' ''Hh'' (figure 7). Vertebrates, on the other hand, have several Hedgehog ligands that fall within three subgroups – ''Desert'', ''Indian'' and ''Sonic'', each represented by a single mammalian gene. This is a consequence of the two rounds of whole genome duplication that occurred early in the vertebrate evolutionary history. Two such events would have produced four homologous genes, one of which must have been lost. Desert Hedgehogs are the most closely related to ''Drosophila'' ''Hh''. Additional gene duplications occurred within some species such as 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 ...
''Danio rerio'', which has an additional ''tiggywinkle hedgehog'' gene in the ''sonic'' group. Various vertebrate lineages have adapted hedgehogs to unique developmental processes. For example, a homologue of the ''X.laevis'' ''banded hedgehog'' is involved in regeneration of the
salamander Salamanders are a group of amphibians typically characterized by their lizard-like appearance, with slender bodies, blunt snouts, short limbs projecting at right angles to the body, and the presence of a tail in both larvae and adults. All ten ...
limb. ''shh'' has undergone accelerated evolution in the primate lineage leading to humans. Dorus ''et al.'' hypothesise that this allowed for more complex regulation of the protein and may have played a role in the increase in volume and complexity of the human brain. The frizzled family of WNT receptors have some sequence similarity to
Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
. Smoothened seems to be a functionally divergent member of the
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCR) superfamily. Other similarities between the WNT and Hh signaling pathways have been reviewed. Nusse observed that, "a signalling system based on lipid-modified proteins and specific membrane translocators is ancient, and may have been the founder of the Wnt and Hh signaling systems". It has been suggested that invertebrate and vertebrate signalling downstream from Smoothened has diverged significantly. The role of Suppressor of Fused (SUFU) has been enhanced in vertebrates compared to ''Drosophila'' where its role is relatively minor. Costal-2 is particularly important in ''Drosophila''. The protein kinase Fused is a regulator of SUFU in ''Drosophila'', but may not play a role in the Hh pathway of vertebrates. In vertebrates, Hh signalling has been heavily implicated in the development of
cilia The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...
. There is striking domain level evolution present in the Hedgehog family of proteins, the N-terminal domain (Hedge) and the C-terminal domain (Hog), that were later spliced together into a single transcriptional unit. The Hog domain contains a sequence called Hint (Hedgehog INTein), which is similar in sequence and function to bacterial and fungal inteins. The Hog domain is present in many eukaryotic branches, i.e. red algae, mosses, dinoflagellates, jakobids, and other single cell eurkaryotes.
Choanoflagellate The choanoflagellates are a group of free-living unicellular and colonial flagellate eukaryotes considered to be the closest living relatives of the animals. Choanoflagellates are collared flagellates, having a funnel shaped collar of interconne ...
s contain a gene named hoglet that also encodes the hedgehog C-terminal domain Hog domain. However, Choanoflagellates and lower eukaryotes do not contain any regions similar to the hedge domain, suggesting that hog evolved first. Poriferans have both hedge-like proteins (termed hedgling) and hog-like proteins, but they exist as two completely separate transcriptional units.
Cnidaria Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter. Their distinguishing feature is cnidocytes, specialized cells that th ...
ns contain the hedgling and hog genes, but also have a complete hedgehog gene, indicating that hedge and hog were spliced into hedgehog after the last common ancestor of poriferans and cnidarians. Bilaterians do not contain hedgling genes, suggesting that these were lost by deletion before this branch split from the other metazoans. However, Hog domain-containing genes without a Hedge domain are present in several bilaterian lineages. They are found in
Lophotrochozoa Lophotrochozoa (, "crest/wheel animals") is a clade of protostome animals within the Spiralia. The taxon was established as a monophyletic group based on molecular evidence. The clade includes animals like annelids, molluscs, bryozoans, brachi ...
and
Nematoda The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a broa ...
. Hedgehog-like genes, 2 Patched homologs and Patched-related genes exist in the worm ''
C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
''. These genes have been shown to code for proteins that have roles in ''C. elegans'' development. Whilst
Enoplea Enoplea (enopleans) is a class, which with the classes SecernenteaTree of Life Web Project (ToL) (2002)Nematoda Version of January 1, 2002. Retrieved November 2, 2008. and Chromadorea make up the phylum Nematoda in current taxonomy. The Enople ...
nematodes have retained a bona-fide Hedgehog,
Chromadorea The Chromadorea are a class of the roundworm phylum, Nematoda. They contain a single subclass (Chromadoria) and several orders. With such a redundant arrangement, the Chromadoria are liable to be divided if the orders are found to form several ...
ns have lost the archetypal Hedgehog and have instead evolved an expanded repertoire of 61 divergent semi-orthologous genes with novel N-terminal domains associated with Hog. These N-terminal domains associated with Hog in ''C. elegans'' were subsequently classified, initially Warthog (WRT) and Groundhog (GRD), followed by Ground-like (GRL) and Quahog (QUA). ''C. elegans'', along with other nematode species, have lost the GPCR Smoothened. The ultimate origin of the Hedgehog signaling pathway is hypothesized to be a bacterial regulatory pathway of
hopanoids Hopanoids are a diverse subclass of triterpenoids with the same hydrocarbon skeleton as the compound hopane. This group of pentacyclic molecules therefore refers to simple hopenes, hopanols and hopanes, but also to extensively functionalized deri ...
that are common
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
components in bacteria and are structural analogs of
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
s.


See also

* Sonic hedgehog, best studied ligand of the vertebrate pathway *
Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
, the conserved
GPCR G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
component of the pathway * Netpath – A curated resource of signal transduction pathways in humans * Inhibitors of Hh signaling **
Cyclopamine Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily ('' Veratrum californicum'') that causes fatal birth defects. It prevents the embryo ...
, a naturally occurring small molecule **
Sonidegib Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer. Sonidegib is Hedgehog signaling pathway inhibitor (via smoothened antagonism). Approvals and indications It was approved for medical use in the United State ...
**
Vismodegib Vismodegib (trade name Erivedge ) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administrati ...
, approved for
basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
.


References


External links

* https://web.archive.org/web/20060716083827/http://hedgehog.sfsu.edu/ (Hedgehog Pathway Database) *http://www.novusbio.com/hedgehogpathway.html (Hedgehog Signaling Pathway Diagram) {{Authority control Cell signaling Evolutionary developmental biology