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

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

  • Dynamic interpretation of hedgehog signaling in the Drosophila wing disc [1]
  • Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb[2]
  • Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud[3] "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.[4]
  • Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long-range, limb-specific SHH enhancer.[5]
  • 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. [6]

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.
  • Regulation of patched by sonic hedgehog in the developing neural tube.[7] "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 - SHH model.jpg
Neural tube - SHH model[8]

Neural Crest

  • Neural crest cell survival in the foregut endoderm of jaw development[9]
  • Sonic hedgehog is required for cardiac outflow tract and neural crest cell development.[10]

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.[11]

Limb

  • 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.

[12]

Limb bud geometry and patterning.jpg
Geometry and patterning of the developing limb bud[13]

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[14]:

  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.

References

  1. <pubmed>19787036</pubmed> | PLOS
  2. <pubmed>19783740</pubmed>
  3. <pubmed>18410737</pubmed>
  4. <pubmed>18327258</pubmed>
  5. <pubmed>18417549</pubmed>
  6. <pubmed>18272593</pubmed>
  7. <pubmed>8790332</pubmed>
  8. <pubmed>20532235</pubmed>
  9. <pubmed>16868080</pubmed>
  10. <pubmed>15936751</pubmed>
  11. <pubmed>19783738</pubmed>
  12. <pubmed>17610861</pubmed> | Dev Biol
  13. <pubmed>20644713</pubmed>| PMC2903596 | PLoS
  14. <pubmed>19399989</pubmed>


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Cite this page: Hill, M.A. (2019, September 23) 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