Developmental Signals - Sonic hedgehog

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Introduction

Sonic.jpg

(SHH, Shh) A secreted growth factor that binds 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.


SHH Links: Sonic hedgehog | Shh receptors | Category:Sonic Hedgehog | Neural System Development
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

Mesenchymal cells of the developing limb bud possess long and highly dynamic cytoplasmic extensions.[1]
  • Divergent axial morphogenesis and early shh expression in vertebrate prospective floor plate[2] "The notochord has organizer properties and is required for floor plate induction and dorsoventral patterning of the neural tube. This activity has been attributed to sonic hedgehog (shh) signaling, which originates in the notochord, forms a gradient, and autoinduces shh expression in the floor plate. However, reported data are inconsistent and the spatiotemporal development of the relevant shh expression domains has not been studied in detail. We therefore studied the expression dynamics of shh in rabbit, chicken and Xenopus laevis embryos (as well as indian hedgehog and desert hedgehog as possible alternative functional candidates in the chicken). ...While shh expression patterns in rabbit and X. laevis embryos are roughly compatible with the classical view of "ventral to dorsal induction" of the floor plate, the early shh expression in the chick floor plate challenges this model. Intriguingly, this alternative sequence of domain induction is related to the asymmetrical morphogenesis of the primitive node and other axial organs in the chick. Our results indicate that the floor plate in X. laevis and chick embryos may be initially induced by planar interaction within the ectoderm or epiblast. Furthermore, we propose that the mode of the floor plate induction adapts to the variant topography of interacting tissues during gastrulation and notochord formation and thereby reveals evolutionary plasticity of early embryonic induction." Chicken Development
  • Disruption of Scube2 impairs endochondral bone formation[3] "SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2) belongs to a secreted and membrane-tethered multi-domain SCUBE protein family composed of 3 members found in vertebrates and mammals. Recent reports suggested that zebrafish scube2 could facilitate sonic hedgehog (Shh) signaling for proper development of slow muscle. However, whether SCUBE2 can regulate the signaling activity of two other hedgehog ligands (Ihh and Dhh), and the developmental relevance of the SCUBE2-induced hedgehog signaling in mammals remain poorly understood. In this study, we first showed that as compared with SCUBE1 or 3, SCUBE2 is the most potent modulator of IHH signaling in vitro. In addition, gain and loss-of-function studies demonstrated that SCUBE2 exerted an osteogenic function by enhancing Ihh-stimulated osteoblast differentiation in the mouse mesenchymal progenitor cells." (More? Bone Development | OMIM611747)
  • GATA6 Is a Crucial Regulator of Shh in the Limb Bud[4] "In the limb bud, patterning along the anterior-posterior (A-P) axis is controlled by Sonic Hedgehog (Shh), a signaling molecule secreted by the "Zone of Polarizing Activity", an organizer tissue located in the posterior margin of the limb bud. We have found that the transcription factors GATA4 and GATA6, which are key regulators of cell identity, are expressed in an anterior to posterior gradient in the early limb bud, raising the possibility that GATA transcription factors may play an additional role in patterning this tissue. While both GATA4 and GATA6 are expressed in an A-P gradient in the forelimb buds, the hindlimb buds principally express GATA6 in an A-P gradient." Limb Development
More recent papers  
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Search term: hedgehog Sonic hedgehog

<pubmed limit=5>Sonic hedgehog</pubmed>

Older papers  
  • Dynamic interpretation of hedgehog signaling in the Drosophila wing disc[5]
  • Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb[6]
  • Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud[7] "One of the first changes we noted was that the dorsoventral polarity of the forebrain was disturbed, which manifested as a loss of Shh in the ventral telencephalon, a reduction in expression of the ventral markers Nkx2.1 and Dlx2, and a concomitant expansion of the dorsal marker Pax6. In addition to changes in the forebrain neuroectoderm, we observed altered gene expression patterns in the facial ectoderm. For example, Shh was not induced in the frontonasal ectoderm, and Ptc and Gli1 were reduced in both the ectoderm and adjacent mesenchyme."
  • THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia.[8]
  • Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long-range, limb-specific SHH enhancer.[9]
  • 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.[10]

Human Hedgehog Family

Table - Human Hedgehog Family
Approved
Symbol
Approved Name Previous
Symbols
Synonyms Chromosome
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  
Table - Human Hedgehog Family
Approved
Symbol
Approved Name Previous
Symbols
Synonyms Chromosome
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


Hedgehog signaling pathway cartoon
Hedgehog signaling pathway[11]

Vertebrates have a number of signaling proteins and receptors that belong to the hedgehog (Hh) family.

Signaling proteins

  1. Desert hedgehog (Dhh)
  2. Indian hedgehog (Ihh)
  3. Sonic hedgehog (Shh)

Receptors

  • Patched homologs - Patched-1 (Ptc1) and Patched-2 (Ptc2)
  • Cubitus interruptus (Ci) homologs - Gli1, Gli2 and Gli3

Functions

Developmental patterning signal.

Neural

Shh frog notochord
Neural tube SHH patterning[12]
  • 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.[13] "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 dorsoventral patterning SHH BMP.jpg

Neural tube cross section dorsoventral domains are established by opposing concentration gradients of Sonic Hedgehog (Shh) and Bone Morphogenic Protein (BMP).[14]

  • 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.


Links: SHH | BMP


Neural tube - SHH model
Neural tube - SHH model[15]

Neural Crest

  • Neural crest cell survival in the foregut endoderm of jaw development[16]
  • Sonic hedgehog is required for cardiac outflow tract and neural crest cell development.[17]

Hearing

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.[18]

Somite

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.[19]

Limb

Mouse hindlimb budsZPA Shh expression.[20]
  • 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.[21]
Limb patterning factors 03.jpg Limb patterning factors 07.jpg
Shh mouse forelimb Template:E11.5[22] Shh mouse hindlimb Template:E12.5[22]
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
Links: Fgf | Hox | Shh | Sox | Limb Development | Mouse Development
Limb bud geometry and patterning.jpg
Geometry and patterning of the developing limb bud[23]

Model GATA6 hindlimb.jpg

Model for GATA6 action Patterning developing Hindlimb Buds[24]

Face

SHH is secreted by the forebrain neuroectoderm and the facial ectoderm for upper face and nasofrontal bud development. PMID: 15979605

Integumentary

SHH is involved with the development of the Merkel cell from progenitor cells in epidermal placodes.

Integumentary touch dome model 01.jpg

A molecular signalling cascade from Wnt, Eda, and Shh is required for touch dome Merkel cell development.[25] Keratin 8 (K8) and Keratin 18 (K18) are Merkel cell markers identified in late fetal and adult skin.

Other

SHH has still others roles in organ development in lung, pancreas.

Signaling Pathway

SHH signaling model

The secreted protein binds to the cell surface membrane protein the patched receptor (ptc).

Canonical Pathway

Series of repressive interactions which culminates in GLI-mediated transcriptional regulation of a variety of cellular processes.

Non-Canonical Pathway

Suggested that there are at least 3 other potential pathways[26]:

  1. Involves hedgehog pathway components but which is independent of GLI-mediated transcription.
  2. Direct interaction of hedgehog signaling components with components of other molecular pathways.
  3. "Non-contiguous" or "atypical" interaction of core hedgehog pathway components with one another.

SHH Receptors

Patched Receptor

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)

BOC/CDON Receptors

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

Megalin

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.

Hedgehog-Interacting Protein

(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.[27]


Abnormalities

Holoprosencephaly

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.[28]

Human holoprosencephaly cyclopia dissection.jpg Proboscis histology.jpg
Human holoprosencephaly cyclopean dissection Proboscis histology
Links: Human holoprosencephaly cyclopia dissection | Proboscis histology | Holoprosencephaly | Neural Abnormalities | Sonic hedgehog


References

  1. Timothy A. Sanders, Esther Llagostera, Maria Barna. Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature Apr 28, 2013.
  2. 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.
  3. 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.
  4. 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.
  5. Nahmad M & Stathopoulos A. (2009). Dynamic interpretation of hedgehog signaling in the Drosophila wing disc. PLoS Biol. , 7, e1000202. PMID: 19787036 DOI.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Bürglin TR. (2008). The Hedgehog protein family. Genome Biol. , 9, 241. PMID: 19040769 DOI.
  12. 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
  13. 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
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 22.0 22.1 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.
  23. Kicheva A & Briscoe J. (2010). Limbs made to measure. PLoS Biol. , 8, e1000421. PMID: 20644713 DOI.
  24. 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.
  25. 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.
  26. Jenkins D. (2009). Hedgehog signalling: emerging evidence for non-canonical pathways. Cell. Signal. , 21, 1023-34. PMID: 19399989
  27. 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.
  28. <pubmed>19563629</pubmed>| PMC2709107


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Cite this page: Hill, M.A. (2019, August 18) Embryology Developmental Signals - Sonic hedgehog. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Sonic_hedgehog

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