The Hedgehog (Hh) family of regulation factors was named after a drosophila (fly) mutant which during embryonic development had prominant changes in regions which should be bare surface cuticle. (More? Flybase HH). The human homolog gene is located on chromosome 7 (7q36) (More? SHH Map) |
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Sonic Hedgehog (SHH) was isolated by homology to the Hh gene. SHH is a true signaling switch used in differentiating subpopulations of cells throughout the embryo. Depending on where the signal is being secreted, how far away the responsive cell population is and how SHH is proteolytically cleaved, will determine SHH function. SHH binds to the membrane receptors Patched (ptc) and BOC/CDON. |
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Cross-sections through early trilaminar frog embryo showing SHH expression (white regions) in the notochord (round structure) and in the overlying floorplate region of the neural plate. (Images- courtesy Lance Davidson) |
Abnormal SHH expression is also thought to lead to the human disorder Holoprosencephaly (More? Neural Abnormalities).
Page Links: Introduction | Some Recent Findings | SHH Patterning | OMIM Entry SHH | Online Textbooks | Human SHH Map | Hedgehog Gene | Patched Receptor | BOC/CDON Receptors | Megalin | Signaling Factors | WWW Links | References | Glossary
Related Pages: Neural Development | Limb Development | Pancreas Development |
Zhu J, Nakamura E, Nguyen MT, Bao X, Akiyama H, Mackem S. Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev Cell. 2008 Apr;14(4):624-32.
Tran PV, Haycraft CJ, Besschetnova TY, Turbe-Doan A, Stottmann RW, Herron BJ, Chesebro AL, Qiu H, Scherz PJ, Shah JV, Yoder BK, Beier DR. THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet. 2008 Apr;40(4):403-10.
Sun M, Ma F, Zeng X, Liu Q, Zhao XL, Wu FX, Wu GP, Zhang ZF, Gu B, Zhao YF, Tian SH, Lin B, Kong XY, Zhang XL, Yang W, Lo W, Zhang X. Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long-range, limb-specific SHH enhancer. J Med Genet. 2008 Apr 16;
Chamberlain CE, Jeong J, Guo C, Allen BL, McMahon AP. Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning. Development. 2008 Mar;135(6):1097-106.
Below are listed some examples of hedgehog signaling in differet regions and tissues of the developing embryo.
Neural Ectodem Ventral neural tube (basal plate, motor columns) Image: dorsoventral axis
Developing Brain
Ectoderm Hair Follicle Development, Tooth Development
Lung Development Image: lung morphogenesis
Pancreas Development
Limb Bud Image: chick limb development | Image: limb patterning molecules
Two ways of viewing the shh entry, a local version from 1999 or the current online entry in the OMIM database.
Local OMIM Entry SHH (1999 version)
OMIM Online Database SHH (current version)
OMIM Online Database PTC (current version)
Text below is modified from Flybase entry for Hedgehog Gene and refers to the fruitfly hh gene. (More? Flybase Entry)
D. melanogaster gene hedgehog , abbreviated as hh.
Encodes a product with the function patched receptor ligand involved in smo receptor signalling pathway which is a component of the plasma membrane
Expressed in the embryo (anal pad , antennal lobe , antennal segment , embryonic/larval anterior spiracle and 13 other listed tissues) and larva (dorsal mesothoracic disc ).
Known homologue in Homo sapiens , Mus , Caenorhabditis elegans , Drosophila and Mus musculus.
Sequenced and its amino acid sequence is also available.
Mapped by recombination to 3-81.2 and cytologically to 94E3 . It interacts genetically with brm , rho , ci , ptc , lin , Ras85D , phl::tor , Ras85D::Src64B , phl , Dsor1 , Dfd , dac , Pka-C1 , bun , E(B)2A , gl , oro , bi , Su(hh)2 to 3A , en , ph-p , fu , Su(fu) , sgl , kn and Wnt4 . There are 87 recorded mutant alleles , of which at least 16 are available from the public stock centers. Amorphic mutations have been isolated which affect the denticle belt and the embryonic epidermis and are embryonic segment polarity recessive lethal. hh is discussed in 602 published references , dated between 1950 and 1999. These include at least 100 studies of mutant phenotypes , 21 studies of wild-type function and 13 molecular studies . Among findings on hh mutants, hh mutants display segment polarity segmentation defects. Among findings on hh function, cell affinities in the adult abdomen depend on hh : cells of the A compartment show two gradients of affinity, both of which depend on direct readouts of the level of hh function. (However, there is much more information on function so that may not be representative.)
Mutant embryos show no obvious segmentation, and are 40% the length of wild type.
Denticles form a lawn arranged in a number of whorls on the ventral surface as a result of loss of naked cuticle.
Search PubMed: term= Hedgehog Gene
Text below is modified from Flybase entry for patched receptor (ptc) and refers to the fruitfly ptc gene. (More? Flybase Entry)
D. melanogaster gene patched is abbreviated as ptc.
Encodes a product with the function patched receptor ligand receptor involved in smo receptor signalling pathway which is a component of the integral plasma membrane protein
Expressed in the embryo (Malpighian tubule , analia , embryonic/larval hindgut , head and 2 other listed tissues)
Known homologue in Homo sapiens , Mus , Caenorhabditis elegans , Drosophila sp. , Mus musculus and Saccharomyces cerevisiae.
Sequenced and its amino acid sequence is also available. It has been mapped by recombination to 2-59 and cytologically to 44D3--4
Interacts genetically with fu , rho , hh , ci , gsb , B , kn , N , l(1)sc , smo , Su(fu) and vn . There are 62 recorded mutant alleles , of which at least 16 are available from the public stock centers.
Amorphic mutations have been isolated which affect the anterior wing , the costal cell , the wing vein and 8 other listed tissues and are embryonic lethal, visible and tissue polarity. ptc is discussed in 325 published references , dated between 1948 and 1999. These include at least 58 studies of mutant phenotypes , one study of wild-type function and 4 molecular studies . Among findings on ptc mutants, ptc mutant analysis and stage-specific laser inactivation of ptc protein indicates that ptc activity is functionally redeployed after the segmentation phenocritical period to discriminate between neural and epithelial cell fates.
Search PubMed: term= Patched Receptor | ptc
Two recently identified related receptors for SHH
BOC - Brother of Cdon
CDON - Cell adhesion molecule-regulated/downregulated by oncogenes)
Boc and Cdon are cell surface receptors of the immunoglobulin (Ig)/fibronectin type III that interact with each other and are coexpressed in development.
Links: OMIM - BROTHER OF CDON | OMIM - CDON
Search PubMed: term= Brother of CDON | CDON
Megalin (also called lipoprotein receptor-related protein-2, LRP2, gp330) is a transmembrane protein which acts as an endocytic receptor on the apical surface of polarised epithelial cells. It requires interaction with another protein, cubulin, for the endocytosis of ligands. In development, it has been shown that sonic hedgehog can also bind megalin and this interaction now requires further research.
Links: OMIM - lipoprotein receptor-related protein-2 | NCBI Bookshelf - Megalin)
Search PubMed: term= Megalin | lipoprotein receptor-related protein-2 | gp330
The image below shows the regional location of the human SHH gene on chromosome 7 (7q36).
Signaling during development, though complex, can also be grouped into a few specific classes. These mechanisms have also been listed and described briefly on Signaling Mechanisms Introduction page.
Okada A, Charron F, Morin S, Shin DS, Wong K, Fabre PJ, Tessier-Lavigne M, McConnell SK. Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature. 2006 Nov 1 "...two Robo-related proteins, Boc and Cdon, bind specifically to Shh and are therefore candidate receptors for the action of Shh as an axon guidance ligand. Boc is expressed by commissural neurons, and targeted disruption of Boc in mouse results in the misguidance of commissural axons towards the floor plate." (More? BOC/CDON Receptors)
Corrales JD, Blaess S, Mahoney EM, Joyner AL. The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development. 2006 May;133(9):1811-21. "Foliation of the mouse cerebellum occurs primarily during the first 2 weeks after birth and is accompanied by tremendous proliferation of granule cell precursors (GCPs). .....Our studies have uncovered a mechanism by which the level and length of Shh signaling could be integral to determining the distinct number of fissures in each species." (Epub 2006 Mar 29.)
Blaess S, Corrales JD, Joyner AL. Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region. Development. 2006 Mar 29 ".... the precise spatial and temporal regulation of Gli2A and Gli3R by Shh is instrumental in coordinating mid/hindbrain development in three dimensions."
Zhou JX, Jia LW, Liu WM, Miao CL, Liu S, Cao YJ, Duan EK. Role of sonic hedgehog in maintaining a pool of proliferating stem cells in the human fetal epidermis. Hum Reprod. 2006 Mar 29 "Shh is an important regulator of human putative epidermal stem cells (HPESC) proliferation in the basal layer of human fetal epidermis and modulates the cell responsiveness to EGF, which will assist to unravel the mechanisms that regulate stem cell proliferation and neoplasia in the human epidermis."
Soundararajan P, Miles GB, Rubin LL, Brownstone RM, Rafuse VF. Motoneurons derived from embryonic stem cells express transcription factors and develop phenotypes characteristic of medial motor column neurons. J Neurosci. 2006 Mar 22;26(12):3256-68. "Embryonic stem (ES) cells differentiate into functional motoneurons when treated with a sonic hedgehog (Shh) agonist and retinoic acid (RA)."
Below are listed some examples of hedgehog signaling in differet regions and tissues of the developing embryo.
Neural Ectodem Ventral neural tube (basal plate, motor columns) Image: dorsoventral axis
Developing Brain
Ectoderm Hair Follicle Development, Tooth Development
Lung Development Image: lung morphogenesis
Pancreas Development
Limb Bud Image: chick limb development | Image: limb patterning molecules
Links: Journals | Online Textbooks | Search Textbooks | PubMed | Search PubMed | Glossary
Developmental Dynamics
Journal of Neurobiology
Developmental Biology (6th ed.) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc. (c2000)
Molecular Biology of the Cell (4th ed.) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing (c2002)
Search NLM Online Textbooks- "hox" : Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach
Reviews
Kayed H, Kleeff J, Osman T, Keleg S, Buchler MW, Friess H. Hedgehog signaling in the normal and diseased pancreas. Pancreas. 2006 Mar;32(2):119-29.
Podlasek CA, Meroz CL, Korolis H, Tang Y, McKenna KE, McVary KT. Sonic hedgehog, the penis and erectile dysfunction: a review of sonic hedgehog signaling in the penis. Curr Pharm Des. 2005;11(31):4011-27.
Levin M. Left-right asymmetry in vertebrate embryogenesis. Bioessays. 1997 Apr;19(4):287-96.
Articles
Zhu J, Nakamura E, Nguyen MT, Bao X, Akiyama H, Mackem S. Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev Cell. 2008 Apr;14(4):624-32.
Tran PV, Haycraft CJ, Besschetnova TY, Turbe-Doan A, Stottmann RW, Herron BJ, Chesebro AL, Qiu H, Scherz PJ, Shah JV, Yoder BK, Beier DR. THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet. 2008 Apr;40(4):403-10.
Chamberlain CE, Jeong J, Guo C, Allen BL, McMahon AP. Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning. Development. 2008 Mar;135(6):1097-106.
Marigo V, et al. Biochemical evidence that patched is the Hedgehog receptor. Nature. 1996 Nov 14;384(6605):176-9.
Marigo V, et al. Regulation of patched by sonic hedgehog in the developing neural tube. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9346-51.
Roessler E, et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet. 1996 Nov;14(3):357-60.
Search PubMed
Search Aug2005 "hedgehog" ?? reference articles of which ?? were reviews.
Search PubMed: term = hedgehog | term = sonic hedgehog | term = patched receptor |
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This section of notes covers specific signaling factors involved in body patterns in multicellular organisms.
Hedgehog is a wonderful story of serendipity and the establishment of linking all species development to similar signals.
Conceptually this mechanism of signaling shows how the same signal can mean different things in different tissues at different times.
Molecular mechanisms of development is an exciting area and requires a variety of different skills. This page introduces only a few examples and should give you a feel for the topic.
Please email Dr Mark Hill if you wish to make a comment about this current project.