Hedgehog


TRANSPARENCY
M. Murone et al., Hedgehog signal transduction: From flies to Vertebrates, Exp. Cell. Res. 253, 25-33, 1999
Drosophila segment polarity gene
Shh (one of several in mammals) controls patterning and is involved in left-right
if gene is missing, cyclopia and many structural defects
cleavage to active 19 kDa N-terminal segment by catalysis by 26-28 kDa C-terminal peptide
N-terminal is palmitoylated at N-terminus and has cholesterol at C-terminus
Patched (Ptc)(12 transmembrane) negative regulator
Smoothened (Smo) positive regulator but it does not bind Shh
Smo is like Frizzled (Wnt/Wingless receptor)
Hh binds to Ptc, Ptc stops repressing Smo
Cubitus interruptus Ci/Gli is a downstream zinc finger transcription factor
target genes: ptc, wb and dpp (decapentaplegic)
Ci-155 active or N-terminal cleaved Ci-75 repressor

PWIngham, Transducing hedgehog: the story so far, EMBO Journal 17, 3505-3511, 1998, on line
Another figure to show the same thing

Steven Dickman, The left-handed gene, Discover 17-8, 70-75, August, 1996.
development from embryonic limb bud
1968 John Sanders showed that transplanted tissue has signal to make digits and polartiy comes from region ZPA (zone of polarizing activity)
Christiane Nusslein-Volhard & Eric Wieschaus 1980-> work on Drosophila
hedgehog - embryo lacking hh is porcupine-like
signal that maintains polarity in segments
Cliff Tabin - Sonic hedgehog is ZPA signal in chicken (because that lab likes loud music)
there's olts of vertebrate hedgehogs like tidiwinkle (who was a hedgehog)
More Sonic on left than right. Change distribution by transplantation, heart not necessarily on left

Mark Peifer, The two faces of hedgehog, Science 266, 1492-1493, 1994
Christiane Nusslein-Volhard & Eric Wieschaus late 1970's did their work which results in the following run-down of types of developmental molecules:
signal - wingless like vertebrate Wnt
receptors - DER Drosophila EGF receptor
transcription factors - Paired like vertebrate Pax
Hedgehog is segment polarity signal

S. S. Blair, Hedgehog digs up an old friend (News and views - Developmental Biology), Nature 373 656-657, 1995
diffusable morphogen
reception via cAMP -> PKA
clones lacking PKA have phenotype like clones expressing hh
expression in posterior cells controls gene expression to the anterior
vertebrate who's who of inducers: notochord, ZPA, floor plate express hh
receptors poorly understood:
Patched (Ptc) in Drosophila transmembrane protein is a candidate
TRANSPARENCY
hh posterior -> anterior Dpp (TGF-beta family) (compartments and eye)
Wingless (Wnt family)

R. L. Johnson & C. Tabin, The long and the short of hedgehog signalling (Minireview), Cell 81 313-316, 1995
morphogens organize cell fates relative to discrete inducing tissue
hh found in 1980 by Nusslein-Volhard and Wieschaus
over short range induce cells to secrete dpp which can act over long range
SHH D - V patterning of neural tube
A - P axis of limb bud
non-cell autonomous consistent with secreted
Processing (1) signal sequence cleavage
(2) self-cleaving into N-terminal (local active) & C-terminal (distance proteolysis)
maybe lower dose for distant effects of second messenger
polarizing activity P limb bud transplanted to anterior limb bud->mirror image extra
SHH mimics ZPA activity (both long and short range

M. Dominguez et al., Sending and receiving the Hedgehog signal: Control by the Drosophila Gli protein Cubitus interruptus, Science 272 1621-1625, 1996
E. Pennisi, Gene linked to commonist cancer (Research News) Science 272 1583-1584, 1996
[Ed. by P. Ssuromi, A patched path to cancer (This Week in Science) Science 272 1561, 1996]
basal cell carcinoma most common cancer:
sporatic in middle age
basal cell nevus syndrome mutant in human homologue of patched gene
Drosophila patched is transmembrane protein which down-regulates
growth factor genes
TRANSPARENCY
GLI (oncogene in rare brain tumor in human) = Ci
cubitus interruptus is a transcription factor
protein from Wnt1 (mice) = Drosophila wg stimulates Hedgehog production
cause mammary tumors when overactive

W. Roush, Hedgehog's patterning call is patched through, smoothly (Developmental biology), Science 274, 1996, 1304-1305
Patched works by interrupting the Smo (smoothened) signal
with Shh, the Smo signal gets through

G. Martin, Pass the butter... (Perspectives), Science 274, 203-204, 1996
hedgehog acts in short and long rang signalling
NH2-terminal (Hh-N) has signalling activity
COOH-terminal (Hh-C) has determinants for autoprocessing
processing is to cleave Hh-N from Hh-C and to attach lipid which, oddly, is cholesterol
It is thought that the cholesterol form, by sticking to membranes would work for short range signalling while a non-modified form would go further

D.I.Lewin, A single gene may tell the embryo left from right (News), Journal of NIH Research, 9 (January), 32- 33, 1997
dorsal-ventral and anterior-posterior better studied than left right in bilaterally "symetric" animals
refers to C. Tabin's work on how there is an asymmetry of shh
maternal mRNA from vegetal 1 (Vg1), in TGF-beta superfamily of diffusable growth factors, processed differently in left and right
also an asymmetry in Xenopus nodal-related 1 (Xnr-1), another maternal mRNA
injection of modified Vg1 containing processing region of bone morphogenic protein 2 (BVg1 mRNA) reverses symmetry
thus symmetry is from differing processings of Vg1 protein
thus there is something like TGF-beta working
chicken nodal-related (cNR), like the mouse nodal required for primitive streak in early embryo, are in TGF-beta family
iv=situs inversus viscerum - regulates Nodal, also:
inv=inversion of embryonic turning (inv)- if mutant mice are reversed for Nodal expression
lefty codes TGF-beta homologue expressed on the left, on right in inv mutant
thus inv important in regulating right-left

References:

M. Murone et al., Hedgehog signal transduction: From flies to Vertebrates, Exp. Cell. Res. 253, 25-33, 1999

PWIngham, Transducing hedgehog: the story so far, EMBO Journal 17, 3505-3511, 1998, on line


Steven Dickman, The left-handed gene, Discover 17-8, 70-75, August, 1996

Mark Peifer, The two faces of hedgehog, Science 266, 1492-1493, 1994

S. S. Blair, Hedgehog digs up an old friend (News and views - Developmental Biology), Nature 373 656-657, 1995

R. L. Johnson & C. Tabin, The long and the short of hedgehog signalling (Minireview), Cell 81 313-316, 1995

M. Dominguez et al., Sending and receiving the Hedgehog signal: Control by the Drosophila Gli protein Cubitus interruptus, Science 272 1621-1625, 1996

W. Roush, Hedgehog's patterning call is patched through, smoothly (Developmental biology), Science 274, 1996, 1304-1305

G. Martin, Pass the butter... (Perspectives), Science 274, 203-204, 1996

D.I.Lewin, A single gene may tell the embryo left from right (News), Journal of NIH Research, 9 (January), 32- 33, 1997

J. D. Axelrod et al. Interaction between Wingless and Notch signalling pathways mediated by disheveled, Science 371 1826-1832, 1996

This page was last updated on March 14, 2002

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