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欢迎随时提问、切磋！
How does a simple cell turn into a complicated organism?
How do genes coordinate and orchestrate the body planning?
Developmental Genetics
•how genes control development
Historical Perspectives
•Classic developmental genetics (1900-1960)
mutant phenotypes > what gene was and how it worked?
•The impact of molecular ideas (1961-1980)
the discovery of mRNA > gene activities are regulated!
•Phenomenon > mechanism
•Mutant phenotype > function of WT gene
•Development > a program encoded in the genome
Basic approaches:
•Saturation mutagenesis
best example: the Nobel-winning Heidelberg screen
•Clonal analysis
track cell lineage, fate, behavior…
An ideal organism to study development
•Short life cycle (~11 days)
•Highly prolific (>100 offsprings / female)
•Genetic details established since T.H. Morgan
•Relatively small genome (~120Mb, 1/11 of cricket’s)
•Only 4 pairs of chromosomes
4d
1d
~hrs
1d
3d
~11days @ 25C
1d
salivary gland chromosomes: 1024 copies
Those who succeed…
…are the most hard-working and persistent.
A Turning Point in the History
of Developmental Genetics
The October 30, 1980 cover
“Mutations Affecting Segment Number and Polarity in Drosophila”
•Phenomenon > mechanism
•Mutant phenotype > function of WT gene
•Development > a program encoded in
the genome
~150 development-regulating genes that affect gross morphology in
Drosophila
stimulated the search for mutant genes affecting development in
other systems (nematode and mouse)
virtually all the genes involved in early development of Drosophila
are represented also in vertebrates
an amazing conservation of regulatory mechanisms across over 600
million years of evolution
The generation of A-P axis
anterior
posterior
WT
Bicoid
Deficient
(maternal)
The hierarchy of
gene action
Examples of gene action
at the molecular levels
3’UTR
contains
localization
signal
Fluorescence resonance energy transfer
Why this is more accurate than single
probe detection?
Denise Montell
D. Godt
The Sekelsky Lab
Visualiztion of oskar mRNA in fly ovary
The molecular mechanism of Hb-gradient formation:
Nanos inhibits Hb translation.
Specific promoter regions of the even-skipped gene
control specific transcription bands in the embryo
eve gene region
How are the repetitive segments made different
from each other?
Why colinearize?
Homeotic gene expression
All transcription factors
homeo ~ similar
The generation of D-V axis
Dorsal
Ventral
Early 80’s: 11 maternal effect mutations isolated
by Anderson & Nusllein-Volhard
Dorsalizing
Phenotype
Rescued by
injecting
mRNA from
WT egg
The gradient of nuclear Dl protein determines D-V polarity
WT
A conserved pathway for regulating nuclear transport of
transcription factors in Drosophila and mammals.
Anderson’s
work
Proximal-distal axis
Fly leg
Based on the previous data obtained by experimental
approaches, can we generate a mathematical model
to predict the unknown?
1. Can we generate a model that fits current data?
2. If a model fits observation, prediction can be made.
3. Prediction has to be validated by experiments.
Reaction-diffusion (Turing model, 1952)
Alan Turing: one of the founders of computer science
A computer simulation based on a
Turing reaction-diffusion system
A photograph of the snail Oliva porphyria (left), and a computer
model of the same snail (right) in which the growth parameters of
the shell and its pigmentation pattern were both mathematically
generated. (From Meinhardt 1998; computer image courtesy of D.
Fowler, P. Prusinkiewicz, and H. Meinhardt.)
A computer simulation based on a
Turing reaction-diffusion system
Actural
pattern
wt
pigmentation enzyme mut
Coputer
model
(From Asai et al. 1999; photographs courtesy of S. Kondo.)
Models can only be as good as the data on
which it is based, genetic analyses are
indispensable for another k years!
A case study
•Name a few morphogens
•How many diverse structures
they’re involved?
Why the haltere doesn’t become another wing?
How is the same morphogen system modulated
to generate diver structures?
Dpp-Z
A
P
Dally: a glypican, or heparin sulfate proteoglycans
Dpp made in the wing is able to travel further from
AP organizer cells than is Dpp made in the
haltere.
Why is that?
1. The Tkv (receptor)-mediated narrowing of the
Dpp activity profile (reflected by pMad) in the
haltere contributes to the smaller size.
2. Differential levels of Dally
dally expression and Dpp signaling
are reduced in the posterior haltere.
Using dally-lacZ as a
reporter,
What’s the phenotype
of Ubx-/-, en-/-, or
antagonizing Dpp
signalling?
What’s the effect
of overexpressing dally?
Your conclusions?
My apologies to all the creators of the
images I downloaded online!
I’m sure they don’t mind sharing their
‘artistic’ works of science.