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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 mutagenesisbest example: the Nobel-winning Heidelberg screen

•Clonal analysistrack 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

~11days @ 25C

1d

1d

1d3d

4d

~hrs

salivary gland chromosomes: 1024 copies

Those who succeed…

…are the most hard-working and persistent.

A Turning Point in the Historyof 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

anterior posterior

The generation of A-P axis

WT

BicoidDeficient(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?

The Sekelsky Lab

Denise Montell

D. Godt

Visualiztion of oskar mRNA in fly ovary

The molecular mechanism of Hb-gradient formation:Nanos inhibits Hb translation.

eve gene region

Specific promoter regions of the even-skipped gene control specific transcription bands in the embryo

How are the repetitive segments made different from each other?

Homeotic gene expression W

hy

coli

nea

rize

?

All transcription factors

homeo ~ similar

The generation of D-V axis

Dorsal

Ventral

DorsalizingPhenotype

Rescued by injecting mRNA from WT egg

Early 80’s: 11 maternal effect mutations isolated by Anderson & Nusllein-Volhard

The gradient of nuclear Dl protein determines D-V polarity

WT dorsaliz

ing

ventralizing

A conserved pathway for regulating nuclear transport of transcription factors in Drosophila and mammals.

Anderson’swork

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 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

wt pigmentation enzyme mut

(From Asai et al. 1999; photographs courtesy of S. Kondo.)

A computer simulation based on a Turing reaction-diffusion system

Acturalpattern

Coputermodel

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?

A P

Dpp-Z

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 signalingare 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 over-expressing 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.