Sonic hedgehog homolog (Drosophila)
3D structure of the signaling domain of the murine Sonic hedgehog from PDB 1vhh
Available structures: 1vhh
Identifiers
Symbol(s)	SHH; HHG1; HLP3; HPE3; SMMCI
External IDs	OMIM: 600725 MGI: 98297 HomoloGene: 30961
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	6469	20423
Ensembl	ENSG00000164690	ENSMUSG00000002633
Uniprot	Q15465	Q8C765
Refseq	NM_000193 (mRNA) NP_000184 (protein)	NM_009170 (mRNA) NP_033196 (protein)
Location	Chr 7: 155.29 - 155.3 Mb	Chr 5: 28.79 - 28.8 Mb
Pubmed search	[1]	[2]

Sonic hedgehog homolog (SHH) is one of three proteins in the mammalian hedgehog family, the others being desert hedgehog (DHH) and Indian hedgehog (IHH). The Protein Data Bank ( PDB) is a repository for 3-D structural data of Proteins and Nucleic acids These data typically obtained by X-ray crystallography The Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome The Mouse Genome Informatics (MGI website is run by The Jackson Laboratory. HomoloGene, a tool of the National Center for Biotechnology Information (NCBI is a system for automated detection of homologs (similarity attributable to descent The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences Ensembl is a joint scientific project between the European Bioinformatics Institute and the Wellcome Trust Sanger Institute, which was launched in 1999 in response to the imminent UniProt is the uni versal prot ein resource a central repository of Protein data created by combining Swiss-Prot, TrEMBL PubMed is a free search engine for accessing the MEDLINE database of citations and abstracts of biomedical research articles Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Mammals ( class Mammalia) are a class of Vertebrate Animals characterized by the presence of Sweat glands, including sweat glands In a growing embryo cells develop differently in the head or tail end of the embryo the left or right and other positions Indian hedgehog homolog (Drosophila, also known as IHH, is a human Gene. SHH is the best studied ligand of the hedgehog signaling pathway. In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally In a growing embryo cells develop differently in the head or tail end of the embryo the left or right and other positions It plays a key role in regulating vertebrate organogenesis, such as in the growth of digits on limbs and organization of the brain. Vertebrates are members of the Subphylum Vertebrata, Chordates with backbones or spinal columns The grouping sometimes includes In animal development, organogenesis is the process by which the Ectoderm, Endoderm, and Mesoderm develop into the Internal organs A limb (from the Old English lim) is a jointed or Prehensile (as Octopus tentacles or new world Monkey tails Appendage of the The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a 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. A morphogen is a substance governing the pattern of tissue development and in particular the positions of the various specialized cell types within a tissue Lewis Wolpert CBE FRS FRSL (born October 19, 1929) is a developmental biologist, Author, and broadcaster The French Flag Model is a conceptual definition of a morphogen described by Lewis Wolpert in the 1960s. Diffusion is the net movement of particles (typically molecules from an area of high concentration to an area of low concentration by uncoordinated random movement An embryo (from Greek:, plural, lit "that which grows" from en- "in" + bryein "to swell be full" is a multicellular SHH remains important in the adult. It controls cell division of adult stem cells and has been implicated in development of some cancers. Cell division is a process by which a cell, called the parent cell divides into two or more cells called daughter cells. Adult stem cells are undifferentiated cells found throughout the body after embryonic development that divide to replenish dying cells and regenerate damaged Carcinogenesis (meaning literally the creation of Cancer) is the process by which normal cells are transformed into cancer cells

Contents 1 Discovery 2 Function 3 Processing 4 Criticism of the name 5 See also 6 References 7 Further reading 8 External links

Discovery

The hedgehog gene (hh) was first identified in the classic Heidelberg screens of Eric Wieschaus and Christiane Nusslein-Volhard, as published in 1978. In a growing embryo cells develop differently in the head or tail end of the embryo the left or right and other positions Eric F Wieschaus (born June 8, 1947) is an American developmental biologist and Christiane Nüsslein-Volhard (born October 20, 1942 in Magdeburg) is a German Biologist who won the Albert Lasker Award 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) embryos. A genetic screen (often shortened to screen) is a procedure or test to identify and select individuals who possess a Phenotype of interest The Nobel Prize in Physiology or Medicine (Nobelpriset i fysiologi eller medicin is awarded once a year by the Swedish Karolinska Institute. Edward B Lewis ( May 20, 1918 &ndash July 21, 2004) was an American Geneticist, the winner of the 1995 Nobel Drosophila melanogaster (from the Greek for black-bellied dew-lover) is a two-winged insect that belongs to the Diptera, the order An embryo (from Greek:, plural, lit "that which grows" from en- "in" + bryein "to swell be full" is a multicellular The hh loss of function mutant phenotype causes the embryos to be covered with denticles (small pointy projections), much like a hedgehog. 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 A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties A hedgehog is any of the small spiny Mammals of the Subfamily Erinaceinae and the order Erinaceomorpha.

Investigations aimed at finding a hedgehog equivalent in mammals revealed three homologous genes. In Evolutionary biology, homology has come to mean any similarity between characters that is due to their shared ancestry. The first two discovered, desert hedgehog and Indian hedgehog, were named for species of hedgehogs, while sonic hedgehog was named after Sega's video game character Sonic the Hedgehog. A hedgehog is any of the small spiny Mammals of the Subfamily Erinaceinae and the order Erinaceomorpha. is a multinational Video game Software and Hardware development company and a former Home computer trademarked Sonic The Hedgehog, is a Video game character and the Protagonist of the video game series released by Sega, as well as in numerous ^[1] In zebrafish, the orthologues of the three mammalian hh genes are: shh a, shh b (formerly described as tiggywinkle hedgehog named for a character from Beatrix Potter's books for children. The zebrafish or zebra danio, Danio rerio, a Tropical Freshwater Fish belonging to the minnow family ( Cyprinidae) In Evolutionary biology, homology has come to mean any similarity between characters that is due to their shared ancestry. ), and indian hedgehog b (formerly described as echidna hedgehog, named for the spiny anteater). Echidnas (ɨˈkɪdnə also known as spiny anteaters, are four extant Mammal species belonging to the Tachyglossidae family of the

Function

Of the hh homologues, shh has been found to have the most critical roles in development, acting as a morphogen involved in patterning many systems, including the limb^[2] and midline structures in the brain^[3] and spinal cord^[4] and the thalamus by the zona limitans intrathalamica^[5]. A morphogen is a substance governing the pattern of tissue development and in particular the positions of the various specialized cell types within a tissue The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain The spinal cord is a long thin tubular bundle of Nerves that is an extension of the Central nervous system from the brain and is enclosed in and protected The thalamus (from Greek θάλαμος = room chamber, IPA= /ˈθæləməs/ is a pair and symmetric part of the brain The zona limitans intrathalamica (ZLI is a transverse boundary located between the Prethalamus (previously also known as ventral thalamus and the functional distinct Thalamus Mutations in the human sonic hedgehog gene, SHH, cause holoprosencephaly type 3 (HPE3) as a result of the loss of the ventral midline. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Holoprosencephaly is a type of Cephalic disorder. This is a disorder characterized by the failure of the Prosencephalon (the Forebrain of the Embryo Sonic hedgehog is secreted by 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. Axon guidance (also called axon pathfinding) is a subfield of Neural development concerning the process by which Neurons send out Axons to reach It has been demonstrated that Shh attracts commissural axons at the ventral midline of the developing spinal cord. ^[6] Specifically, Shh attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations. A ganglion cell (more correctly a retinal ganglion cell or RGC) is a type of Neuron typically located near the inner surface of the Retina ^[7] The absence (non-expression) of Shh has been shown to control the growth of nascent hind limbs in cetaceans^[8] (whales and dolphins). The Order Cetacea (sɪˈteɪʃiə L cetus, whale includes Whales Dolphins and Porpoises Cetus is Whales are marine mammals which are neither Dolphins (ie members of the families Delphinidae or Platanistoidae) nor Porpoises Orcas Dolphins are Marine mammals that are closely related to Whales and Porpoises There are almost forty species of dolphin in seventeen genera.

Processing

SHH undergoes a series of processing steps before it is secreted from the cell. Newly synthesised SHH weighs 45 kDa and is referred to as the preproprotein. The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express 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. A signal peptide is a short (3-60 Amino acids long Peptide chain that directs the post- translational transport of a Protein. The signal recognition particle (SRP is a Ribonucleoprotein ( Protein - RNA complex that recognizes and transports specific proteins to the Endoplasmic The endoplasmic reticulum (Greek endo = "within" (prefix plásma = "formed entity" Latin reticulum = "little net" or ER, is an Organelle Secretion is the process of segregating elaborating and releasing chemicals from a cell, or a secreted Chemical substance or amount of substance Once translocation is complete, the signal sequence is removed by signal peptidase in the ER. The Signal Peptide Peptidase (SPP and its Homologs (SPPL2a/b/c SPPL3 are a class of transmembrane Aspartyl proteases with the conserved motives YD. 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. ^[9] The cleavage is catalysed by a protease within the C-terminal domain. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link During the reaction, a cholesterol molecule is added to the C-terminus of SHH-N. Cholesterol is a Lipid found in the Cell membranes and transported in the Blood plasma of all Animals It is an essential component of mammalian ^[10] Thus the C-terminal domain acts as an intein and a cholesterol transferase. An intein is a segment of a Protein that is able to excise itself and rejoin the remaining portions (the exteins with a Peptide bond. Another hydrophobic moiety, a palmitate, is added to the alpha-amine of N-terminal cysteine of SHH-N. In Chemistry, hydrophobicity (from the combining form of water in Attic Greek hydro- and for fear phobos) refers to the physical property of Palmitic acid,CH3(CH214COOH or hexadecanoic acid in IUPAC nomenclature, is one of the most common saturated Fatty acids found in animals Not to be confused with Cystine, its oxidized dimer Cysteine (abbreviated as Cys or C) is an α- Amino acid with This modification is required for efficient signaling, resulting in 30-fold increase in potency over the non-palmitylated form. ^[11]

Criticism of the name

Some clinicians and scientists criticize giving genes frivolous or quirky names, calling it inappropriate that patients with "a serious illness or disability are told that they or their child have a mutation in a gene such as Sonic hedgehog. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism "^[12] Others see black humour in the gene responsible for holoprosencephaly being named for a character who is arguably holoprosencephalic, being drawn with fused eyes or cyclopia. Cyclopia (also cyclocephaly or synophthalmia) is a rare form of Holoprosencephaly and is a Congenital disorder (birth defect characterized by

See also

• Zbtb7, a gene which was originally named Pokemon after the video game Pokémon

References

Further reading

External links

• An introductory article on shh at Davidson College
• SHH at The GDB Human Genome Database
• Rediscovering biology: Unit 7, Genetics of development. Expert interview transcripts, interview with John Incardona, PhD. Davidson College is a private liberal arts college for 1700 students in Davidson, North Carolina, in the United States. explanation of the discovery and naming of the sonic hedgehog gene
• ‘Sonic Hedgehog’ sounded funny, at first. New York Times, November 12, 2006.

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