Developmental Signals - Sonic hedgehog
|Embryology - 20 Apr 2021 Expand to Translate|
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The secreted growth factor sonic hedgehog (SHH, Shh) binds the patched (ptc) receptor on cell membrane. This protein has many different functions in different tissues of the developing embryo, the main role would be of establishing "pattern". SHH name derives from homology to the original fruitfly (drosophila) "hedgehog" mutation, where these flies have hairs located in regions (ventral) which are normally hair-free, and therefore have a disrupted body pattern.
Sonic Hedgehog was isolated by homology to the Hedgehog (Hh) gene. A single Hh homolog is present in Drosophila, but three Hh homologs, Sonic Hh, Indian Hh, and Desert Hh, are present in mammals.
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.
Nomenclature note - upper case SHH in humans, lower case shh used for other species.
|Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular|
Some Recent Findings
|More recent papers|
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.
Search all databases: sonic hedgehog
|These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.
Human Hedgehog Family
|Table - Human Hedgehog Family|
|DHH||desert hedgehog||"HHG-3, MGC35145"||12q13.12|
|IHH||indian hedgehog||"HHG2, BDA1"||2q35|
|SHH||sonic hedgehog||"HPE3, HLP3"||"HHG1, SMMCI, TPT, TPTPS, MCOPCB5"||7q36.3|
|Links: sonic hedgehog | OMIM Fgf1 | HGNC | Bmp Family | Fgf Family | Hedgehog Family | Sox Family | Tbx Family|
|Human Hedgehog Family|
Vertebrates have a number of signaling proteins and receptors that belong to the hedgehog (Hh) family.
- Desert hedgehog (Dhh)
- Indian hedgehog (Ihh)
- Sonic hedgehog (Shh)
- Patched homologs - Patched-1 (Ptc1) and Patched-2 (Ptc2)
- Cubitus interruptus (Ci) homologs - Gli1, Gli2 and Gli3
Developmental patterning signal.
- SHH is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons.
- Regulation of patched by sonic hedgehog in the developing neural tube. "The pattern of PTC expression suggests that Sonic hedgehog may play an inductive role in more dorsal regions of the neural tube than have been previously demonstrated. Examination of the pattern of PTC expression also suggests that PTC may act in a negative feedback loop to attenuate hedgehog signaling."
Neural tube cross section dorsoventral domains are established by opposing concentration gradients of Sonic Hedgehog (Shh) and Bone Morphogenic Protein (BMP).
- left - These regulate progenitor gene expression. The progenitor genes cross-repress each other to establish domain boundaries.
- right - Each domain will give rise to a specific cell type that expresses various post-mitotic differentiation genes.
|Neural tube - SHH model|
|A model of mouse cranial nerve development includes SHH action during neural crest cell migrating from rhombomere 2 (r2) or 4 (r4) interaction with placodal cells to develop the cranial nerves.|
- Neural crest cell survival in the foregut endoderm of jaw development
- Sonic hedgehog is required for cardiac outflow tract and neural crest cell development.
During mouse cochlea development the adjacent auditory (spiral) ganglion acts as a source of Sonic hedgehog. Without SHH the cochlear duct is shortened, sensory hair cell precursors prematurely leave the mitotic cell cycle, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction.
A study has shown an essential role for Shh signalling in the control of laminin-111 synthesis and in the initiation of basement membrane assembly in the myotome.
- SHH is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation.
- Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb.
|Shh mouse forelimb E11.5||Shh mouse hindlimb E12.5|
- Mouse Limb Images: Tbx3 and Tbx2 forelimb E10 | Alx3 and Gli3 forelimb E10 | Fgf and Hox forelimb E10.5 | Bmp4 forelimb E11.5 | Bmp4 hindlimb E11.5 | Shh forelimb E11.5 | Fgf8 hindlimb E11.5 | Sox9 forelimb E12.5 | Msx2 forelimb E12.5 | Shh hindlimb E12.5
|Geometry and patterning of the developing limb bud|
Model for GATA6 action Patterning developing Hindlimb Buds
Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces chondrogenesis of rabbit bone marrow stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation."
- Links: cartilage
SHH is secreted by the forebrain neuroectoderm and the facial ectoderm for upper face and nasofrontal bud development.
Components of the Shh pathway are localized in the palatal epithelium, though inhibition of Shh signaling in palatal epithelium does not affect palatogenesis. A recent mouse study with constitutive activation of hedgehog signaling results in submucous cleft palate and persistence of the medial edge epithelium (MEE). Precise down-regulation of Shh signaling is required in the MEE during palatal fusion, persistence may prevent MEE cells apoptosis.
SHH is involved with the development of the Merkel cell from progenitor cells in epidermal placodes.
A molecular signalling cascade from Wnt, Eda, and Shh is required for touch dome Merkel cell development. Keratin 8 (K8) and Keratin 18 (K18) are Merkel cell markers identified in late fetal and adult skin.
SHH has still others roles in organ development in lung, pancreas.
The secreted protein binds to the cell surface membrane protein the patched receptor (ptc).
Series of repressive interactions which culminates in GLI-mediated transcriptional regulation of a variety of cellular processes.
Suggested that there are at least 3 other potential pathways:
- Involves hedgehog pathway components but which is independent of GLI-mediated transcription.
- Direct interaction of hedgehog signaling components with components of other molecular pathways.
- "Non-contiguous" or "atypical" interaction of core hedgehog pathway components with one another.
In the fly, D. melanogaster, patched (ptc) is a protein ligand receptor involved in the smo receptor signalling pathway which is a component of the integral plasma membrane protein. There are homologues in Homo sapiens , Mus , Caenorhabditis elegans , Drosophila sp. , Mus musculus and Saccharomyces cerevisiae.
D. melanogaster expression in the embryo (Malpighian tubule , analia , embryonic/larval hindgut , head and 2 other listed tissues). Protein 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. (Some text modified from Flybase entry for Hedgehog Gene and refers to the fruitfly hh gene)
Two recently identified related receptors for SHH, Boc and Cdon are cell surface receptors of the immunoglobulin (Ig)/fibronectin type III that interact with each other and are coexpressed in development.
- Brother of Cdon (BOC) OMIM 608708
- Cell adhesion molecule-regulated/downregulated by oncogenes (CDON) OMIM 608707
In development, it has been shown that sonic hedgehog can also bind megalin (lipoprotein receptor-related protein-2, LRP2, gp330) 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.
(HHIP) A surface receptor antagonist that is equipotent against all three mammalian Hh homologs. The structure of human HHIP is comprised of two EGF domains and a six-bladed beta-propeller domain.
HHIP1 is secreted by cells during embryo development and binds heparan sulfate (HS) extracellularly to antagonise the HH pathway and therefore restricts the HH ligand function.
Defects in the SHH protein or its signalling pathway are a cause of Holoprosencephaly (International Classification of Diseases - Q04 Other congenital malformations of brain - Q04.2 Holoprosencephaly).
Below are shown images of human fetal holoprosencephaly and associated cyclopia.
|Human holoprosencephaly cyclopean dissection||Proboscis histology|
- Links: Human holoprosencephaly cyclopia dissection | Proboscis histology | Holoprosencephaly | Neural Abnormalities | Sonic hedgehog
- Sanders TA, Llagostera E & Barna M. (2013). Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature , 497, 628-32. PMID: 23624372 DOI.
- Yabut OR, Ng HX, Yoon K, Arela JC, Ngo T & Pleasure SJ. (2020). The neocortical progenitor specification program is established through combined modulation of SHH and FGF signaling. J. Neurosci. , , . PMID: 32737167 DOI.
- Chen L, Liu G, Li W & Wu X. (2019). Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system. BMC Dev. Biol. , 19, 18. PMID: 31401976 DOI.
- Sagai T, Amano T, Maeno A, Ajima R & Shiroishi T. (2019). SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization. Proc. Natl. Acad. Sci. U.S.A. , , . PMID: 31685615 DOI.
- Ankamreddy H, Min H, Kim JY, Yang X, Cho ES, Kim UK & Bok J. (2019). Region-specific endodermal signals direct neural crest cells to form the three middle ear ossicles. Development , 146, . PMID: 30630826 DOI.
- Li J, Yuan Y, He J, Feng J, Han X, Jing J, Ho TV, Xu J & Chai Y. (2018). Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion. Dev. Biol. , 441, 191-203. PMID: 29981310 DOI.
- Qi X, Schmiege P, Coutavas E, Wang J & Li X. (2018). Structures of human Patched and its complex with native palmitoylated sonic hedgehog. Nature , , . PMID: 29995851 DOI.
- Cheng FY, Fleming JT & Chiang C. (2018). Bergmann glial Sonic hedgehog signaling activity is required for proper cerebellar cortical expansion and architecture. Dev. Biol. , 440, 152-166. PMID: 29792854 DOI.
- Kremnyov S, Henningfeld K, Viebahn C & Tsikolia N. (2018). Divergent axial morphogenesis and earlyshhexpression in vertebrate prospective floor plate. Evodevo , 9, 4. PMID: 29423139 DOI.
- Lin YC, Roffler SR, Yan YT & Yang RB. (2015). Disruption of Scube2 Impairs Endochondral Bone Formation. J. Bone Miner. Res. , 30, 1255-67. PMID: 25639508 DOI.
- Kozhemyakina E, Ionescu A & Lassar AB. (2014). GATA6 is a crucial regulator of Shh in the limb bud. PLoS Genet. , 10, e1004072. PMID: 24415953 DOI.
- Nahmad M & Stathopoulos A. (2009). Dynamic interpretation of hedgehog signaling in the Drosophila wing disc. PLoS Biol. , 7, e1000202. PMID: 19787036 DOI.
- Butterfield NC, Metzis V, McGlinn E, Bruce SJ, Wainwright BJ & Wicking C. (2009). Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development , 136, 3515-24. PMID: 19783740 DOI.
- Zhu J, Nakamura E, Nguyen MT, Bao X, Akiyama H & Mackem S. (2008). Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev. Cell , 14, 624-32. PMID: 18410737 DOI.
- 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. (2008). THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat. Genet. , 40, 403-410. PMID: 18327258 DOI.
- 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 WH & Zhang X. (2008). Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer. J. Med. Genet. , 45, 589-95. PMID: 18417549 DOI.
- Chamberlain CE, Jeong J, Guo C, Allen BL & McMahon AP. (2008). 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 , 135, 1097-106. PMID: 18272593 DOI.
- Bürglin TR. (2008). The Hedgehog protein family. Genome Biol. , 9, 241. PMID: 19040769 DOI.
- Fogarty P, Campbell SD, Abu-Shumays R, Phalle BS, Yu KR, Uy GL, Goldberg ML & Sullivan W. (1997). The Drosophila grapes gene is related to checkpoint gene chk1/rad27 and is required for late syncytial division fidelity. Curr. Biol. , 7, 418-26. PMID: 9197245
- Marigo V & Tabin CJ. (1996). Regulation of patched by sonic hedgehog in the developing neural tube. Proc. Natl. Acad. Sci. U.S.A. , 93, 9346-51. PMID: 8790332
- Zannino DA & Sagerström CG. (2015). An emerging role for prdm family genes in dorsoventral patterning of the vertebrate nervous system. Neural Dev , 10, 24. PMID: 26499851 DOI.
- Dessaud E, Ribes V, Balaskas N, Yang LL, Pierani A, Kicheva A, Novitch BG, Briscoe J & Sasai N. (2010). Dynamic assignment and maintenance of positional identity in the ventral neural tube by the morphogen sonic hedgehog. PLoS Biol. , 8, e1000382. PMID: 20532235 DOI.
- Kurosaka H, Trainor PA, Leroux-Berger M & Iulianella A. (2015). Cranial nerve development requires co-ordinated Shh and canonical Wnt signaling. PLoS ONE , 10, e0120821. PMID: 25799573 DOI.
- Brito JM, Teillet MA & Le Douarin NM. (2006). An early role for sonic hedgehog from foregut endoderm in jaw development: ensuring neural crest cell survival. Proc. Natl. Acad. Sci. U.S.A. , 103, 11607-12. PMID: 16868080 DOI.
- Washington Smoak I, Byrd NA, Abu-Issa R, Goddeeris MM, Anderson R, Morris J, Yamamura K, Klingensmith J & Meyers EN. (2005). Sonic hedgehog is required for cardiac outflow tract and neural crest cell development. Dev. Biol. , 283, 357-72. PMID: 15936751 DOI.
- Bok J, Zenczak C, Hwang CH & Wu DK. (2013). Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells. Proc. Natl. Acad. Sci. U.S.A. , 110, 13869-74. PMID: 23918393 DOI.
- Anderson C, Thorsteinsdóttir S & Borycki AG. (2009). Sonic hedgehog-dependent synthesis of laminin alpha1 controls basement membrane assembly in the myotome. Development , 136, 3495-504. PMID: 19783738 DOI.
- Galli A, Robay D, Osterwalder M, Bao X, Bénazet JD, Tariq M, Paro R, Mackem S & Zeller R. (2010). Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet. , 6, e1000901. PMID: 20386744 DOI.
- Scherz PJ, McGlinn E, Nissim S & Tabin CJ. (2007). Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb. Dev. Biol. , 308, 343-54. PMID: 17610861 DOI.
- Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V & Tabin CJ. (2006). Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. , 2, e216. PMID: 17194222 DOI.
- Kicheva A & Briscoe J. (2010). Limbs made to measure. PLoS Biol. , 8, e1000421. PMID: 20644713 DOI.
- Kozhemyakina E, Ionescu A & Lassar AB. (2014). GATA6 is a crucial regulator of Shh in the limb bud. PLoS Genet. , 10, e1004072. PMID: 24415953 DOI.
- Marcucio RS, Cordero DR, Hu D & Helms JA. (2005). Molecular interactions coordinating the development of the forebrain and face. Dev. Biol. , 284, 48-61. PMID: 15979605 DOI.
- Billmyre KK & Klingensmith J. (2015). Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation. Dev. Dyn. , 244, 564-76. PMID: 25626636 DOI.
- Lan Y & Jiang R. (2009). Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth. Development , 136, 1387-96. PMID: 19304890 DOI.
- Kurosaka H, Iulianella A, Williams T & Trainor PA. (2014). Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis. J. Clin. Invest. , 124, 1660-71. PMID: 24590292 DOI.
- Xiao Y, Thoresen DT, Miao L, Williams JS, Wang C, Atit RP, Wong SY & Brownell I. (2016). A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development. PLoS Genet. , 12, e1006150. PMID: 27414798 DOI.
- Jenkins D. (2009). Hedgehog signalling: emerging evidence for non-canonical pathways. Cell. Signal. , 21, 1023-34. PMID: 19399989
- Holtz AM, Griffiths SC, Davis SJ, Bishop B, Siebold C & Allen BL. (2015). Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function. J. Cell Biol. , 209, 739-57. PMID: 26056142 DOI.
- <pubmed>19563629</pubmed>| PMC2709107
Groves I, Placzek M & Fletcher AG. (2020). Of mitogens and morphogens: modelling Sonic Hedgehog mechanisms in vertebrate development. Philos. Trans. R. Soc. Lond., B, Biol. Sci. , 375, 20190660. PMID: 32829689 DOI.
Liao H, Cai J, Liu C, Shen L, Pu X, Yao Y, Han B, Yu T, Cheng SY & Yue S. (2020). Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused. Cell Death Dis , 11, 686. PMID: 32826873 DOI.
Billmyre KK & Klingensmith J. (2015). Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation. Dev. Dyn. , 244, 564-76. PMID: 25626636 DOI.
Yamagishi C, Yamagishi H, Maeda J, Tsuchihashi T, Ivey K, Hu T & Srivastava D. (2006). Sonic hedgehog is essential for first pharyngeal arch development. Pediatr. Res. , 59, 349-54. PMID: 16492970 DOI.
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- OMIM - Sonic hedgehog
- EMBL UniProt - Sonic hedgehog protein
- PubMed - Crystal Structure Of Human Sonic Hedgehog N-Terminal Domain
- Genetics Home Reference. - SHH
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