Developmental Signals - Sonic hedgehog

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Introduction

Sonic.jpg

(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 (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.

Nomenclature note lower case shh for other species, upper case SHH in humans.

Some Recent Findings

  • Dynamic interpretation of hedgehog signaling in the Drosophila wing disc. Nahmad M, Stathopoulos A. PLoS Biol. 2009 Sep;7(9):e1000202. Epub 2009 Sep 29. PMID: 19787036 | PLOS
  • Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Butterfield NC, Metzis V, McGlinn E, Bruce SJ, Wainwright BJ, Wicking C. Development. 2009 Oct;136(20):3515-24. PMID: 19783740
  • 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. PMID: 18410737
"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."
  • 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. PMID: 18327258
  • 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 PMID: 18417549
  • 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. PMID: 18272593

Functions

Developmental patterning signal.

Neural

Shh frog notochord

SHH is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons.

  • neural crest cell survival in the foregut endoderm of jaw development PNAS
Neural tube - SHH model.jpg
Neural tube - SHH model[1]

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.[2]

Limb

SHH is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation.

Face

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

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[3]:

  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.

References

  1. <pubmed>20532235</pubmed>
  2. <pubmed>19783738</pubmed>
  3. <pubmed>19399989</pubmed>


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Cite this page: Hill, M.A. (2019, October 22) Embryology Developmental Signals - Sonic hedgehog. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Sonic_hedgehog

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© Dr Mark Hill 2019, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G