I'm rather fond of this material. Partly because my work introduced the sevenless gene. At the time, the sevenless mutation was used to show that R7 is a UV receptor.

Know from earlier courses:
induction important "optic vesicle"
TRANSPARENCY from introductory textbook (like Fig. 22-2, p. 1141 Alberts)
signifies that retina is outgrowth of CNS
know that induction from retina makes ectoderm turn into lens placode

Drosophila is a model for understanding development, generally
Lewis, Weichaus, Nusslein-Volhard - 1995 Nobel Prize
Order of action: maternal genes, zygotic genes, homeotic genes
Imaginal discs TRANSPARENCY
(introductory book version of Fig. 21-71 p. 1097 Alberts)
homeotic mutants TRANSPARENCY
(introductory textbook version of Fig. 21-67, p. 1093 Alberts - antennapedia)
homeotic gene has homeobox (183 bp of DNA),
DNA binding protein has homeodomain (helix turn helix)

R. Mestel, Secrets in a fly's eye, Discover (July, 1996) 106-114
useful to introduce the ommatidial structure first
TRANSPARENCY - diagram from Cagan (now at Wash. U) and Zipursky
How do > 750 ommatidia with some 19 cells develop?
(receptors (R1-6, R7 & R8, cone cells, bristles, pigment cells)
Benzer (late 1960's) started screen for receptor mutants (like sev)
(vision is not essential [for mating] in Drosophila melanogaster)
Ready - 1976 - showed usefulness of imaginal disk in development
TRANSPARENCY - development in the eye imaginal disk
morphogenetic furrow
American plans of development- who your neighbors are is important
vs European (exemplified inC. elegans where lineage is important
- 1986 - showed in sev that R7 precursor becomes cone cell
Rubin - early 1980's - step up molecular developmental approach
Later, Zipursky, Banerjee, Simon, many others
Walter Gehring (Basel) fly eyeless like small eye mouse and aniridia in human, PAX-6 gene
eye development in fly, human, mouse, flatworm, squid may have common control even though different eyes had been previously thought of as being an example of convergent evolution

tyrosine kinase signalling
small G protein
sevenless signalling pathway
TRANSPARENCY Fig. 15-52, p. 764 - sequential addition of receptor cells in Drosophila eye: R8, R2 & R5, R3 & R4, R1& R8, R7
TRANSPARENCY Fig. 15-53, p. 765 Alberts et al. early R7 signalling steps
Boss = bride of sevenless is 7 transmembrane domain ligand
C-terminal intracellular, N-terminal extracellular
sevenless is receptor tyrosine kinsae -
2 transmembrane subunits, 2 extracellular subunits
expressed everywhere except R2 R5 and R8
It is a topic of intense present interest how this signals across membrane
Drk = downstream of receptor tyrosine kinase
which is a small SH adaptor protein, SH = src homology
src = oncogene of Roux sarcoma virus
Sos = son of sevenless
which is a GNRP (guanine nucleotide releasing protein)
to exchange GTP for GDP on ras
ras = rat sarcoma [viral ras oncogene of normal protooncogene]
ras is actually linked to membrane by fatty acid
GAP (sextra in Drosophila) does opposite (GTPase activating protein)

TRANSPARENCY (my drawing)
other steps -> signalling to nucleus
MAPK = mitogen activated protein kinase
alias ERK = extracellular signal regulated kinase

TRANSPARENCY Fig. 1 from Yamamoto, another diagram of the cellular architecture of the Drosophila compound eye
TRANSPARENCY from Cagan and Zipursky showing sequential recruitments of receptors plus cone cells and pigment cells
TRANSPARENCY a table from Yamamoto listing genes, phenotypes, gene products and developmental roles for sev, boss, ro, svp, drk, Sos, ras, sina, raf, Dsor, rl, and others
TRASPARENCY diagram of the sev signalling pathway from Yamamoto
TRANSPARENCY from Moses showing expression patterns of several genes (rough, glass, seven-up, sina) which are transcription factors (cf. Yamamoto table)

ras oncogenes may be involved in 30% of human cancers. mutations usually block GTPase or GAP stimulation
the 21 refers to 21 kDa
Raf=MAPKK first found from v-raf retroviral oncogene
there is a c-raf proto-oncogene
ras is localized to plasma membrane by fatty acid
suggestion that ras's function is to bring raf to the membrane
TRANSPARENCY from Marshall showing interactions with SH2 and SH3 domains in GAP and Switch I and Switch II in p21ras which is reminescent of structural work on alpha subunit of G protein (e.g. Lambright, et al., covered earlier this semester, Nature 369, 1994, 621-628)


R.L.Cagan and S.L.Zipursky, Cell choice and patterning in the Drosophila retina, in Determinations of Neuronal Identity (eds. M. Shankland and E.R.Macagno) NY, Academic Press, 1992. (not on reserve)

A. Hall, A biochemical function for ras - at last, Science, 264, 1413-1414, 1994

M.S.Marshall, The effector interactions of p21ras (Review), Trends in Biochemical Sciences, 1993, 18, 250-255.

R. Mestel, Secrets in a fly's eye, Discover (July, 1996) 106-114

K. Moses, The role of transcription factors in the developing Drosophila eye, Trends in Genetics, 7#8, 250-255, 1991 (not on reserve)

D. Stokoe et al., Activation of Raf as a result of recruitment to the plasma membrane, Science, 264, 1463-1467, 1994

D. Yamamoto, Signaling mechanisms in induction of the R7 photoreceptor in the developing Drosophila retina (Review Article) BioEssays 16 #4, 1994, 237-244

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