Download Overview of Drosophila development

SBC Networks Journal Club – June 19, 2002
George von Dassow, et al. The segment polarity network is a robust developmental
module, Nature 406, 13 July 2000, pp 188-192
Main Points
The gene regulation of development in Drosophila melanogaster has been
exhaustively studied over two decades.
A subset of five (out of 10-20) genes involved in segment polarity determination was
selected for modelling. Interactions of these five genes were abstracted from the
literature.
A simulated embryo was constructed with hexagonal cells, and ‘wrap-around’
boundary conditions.
State variables were concentrations of genes, proteins, and transformed proteins, in
each cell of the simulation
Initial conditions were set based on experimental data
State variables were normalized (non-dimensionalized) relative to their maximum
attainable values in a single cell.
Each cell was considered homogenous. A system of 13 differential equations for state
variables reflected the abstracted system
There were 49 non-dimensional parameters; previously measured values for
analogous parameters, non-dimensionalized, would span two to three orders of
magnitude.
Logarithms of parameters were independently sampled from the possible ranges.
Even with ‘perfect’ initial conditions, no model produced polarity distributions
resembling experimental data
The writers chose to add in several postulated interactions to make the dynamical
system more stable.
With these additional interactions approximately 1 in 200 of systems with randomly
selected parameters, and ‘perfect’ initial conditions, show stable segregation that
strongly resembles experimental data on these five genes.
Several forms of ‘degraded’ initial conditions also led to lesser, but still positive,
numbers of good solutions.
A short calculation shows that if the system could tolerate only a 10% variation
(relative to log-range) in each parameter independently, then only 1 in 1048 would be
expected to work.
The conclusion was that the segment polarity network is robust
An American-style (too fast) Overview of Drosophila development
(Cribbed from Genetic Control of Segmentation in Drosophila
http://www.ucalgary.ca/UofC/eduweb/virtualembryo/D_m_segment_II.html, by
Dr. William Brook Department of Biochemistry and Molecular Biology,
University of Calgary )
See also Sean B. Carroll et al, From DNA to Diversity
Overview
The fertilized egg of Drosophila melanogaster gives rise to a segmented fullydifferentiated maggot over the course of a 24 hour embryonic period. The genetic
control of segmentation involves a cascade of gene regulation occurring largely
before the onset of the cellular blastoderm stage (~2.5 to 3 hours of development).
The cascade (Fig. 1) begins with the diffusion of spatially localized maternal factors,
the products of the coordinate genes (i.e. bicoid, nanos, caudal, etc.), from the
anterior and posterior poles of the embryo. These control the spatial patterns of
transcription of the gap genes (i.e. hunchback. Krüppel, knirps, etc.). The gap genes
are amongst the earliest expressed zygotic genes and they encode transcription
factors. The gap genes are expressed overlapping territories along the anterior to
posterior axis of the fly embryo. These genes act to sub-divide the embryo into broad
domains (anterior, middle, posterior). Each domain encompasses the progenitors of
several contiguous segments. The gap genes regulate each other and the next set of
genes in the hierarchy, the pair-rule genes (even-skipped, hairy, fushi-tarazu, etc.).
Pair-rule genes are expressed in 7 stripes of cells corresponding to every other
segment. Pair-rule genes encode transcription factors that establish the expression
of the segment polarity genes (wingless, hedgehog, engrailed, etc.), many of
which are expressed in 14 segmentally repeated stripes. Unlike the other classes of
segmentation genes, the segment polarity genes include regulatory proteins other
than transcription factors (i.e. secreted signaling molecules, receptors, kinases, etc.)
and they mediate interactions between cells. The end result of the hierarchy is a
series of segments that have identical repeated segment polarity gene expression
patterns. The final group of genes are the homeotic genes which control the
character (i.e. head, thorax, abdomen) of each segment.
Pair-rule genes (i.e. even-skipped, fushi tarazu)
The embryo is divided into large regions by the expression of the gap genes; these
and the co-ordinate genes in turn activate transcription of the pair-rule genes in
seven stripes. There is a separate enhancer controlling the expression of each stripe
of gene expression in each of the primary pair-rule genes. So upstream of evenskipped there are 7 independent regulatory elements - one for each stripe. The three
primary pair-rule genes (even-skipped, hairy, and runt) are expressed in 7 stripes
each for a total of 21 over-lapping domains of gene expression, and these three
genes regulate the expression of the secondary pair-rule genes (fushi-tarazu, oddskipped, odd-paired, paired, and others) .
First phase of segment polarity gene expression: pair-rule genes establish
segment polarity gene expression patterns
The primary pair-rule gene expression patterns are established by the coordinate and
gap genes and then refined through interactions with each other and with the
secondary pair-rule genes. For example, even-skipped (eve) represses the
expression of fushi-tarazu (ftz)leading to the expression of the two genes in
complementary graded patterns of expression in alternating parasegments.
The pair-rule genes are already expressed in a periodic pattern, so it is easy to
imagine how they establish the segment polarity gene expression in every
parasegment. The expression patterns of the segment polarity genes engrailed (en)
and wingless (wg) are established through positive and negative transcriptional
regulation by the pair-rule genes. For example, the expression of en is activated by
either Ftz or Eve in each parasegment, whereas wingless is repressed by Ftz or Eve
in each parasegment.
Other pair-rule genes also control wg and en expression. For example, paired and
odd-paired are responsible for the activation of engrailed AND wingless in
alternating stripes.
Second phase of segment polarity gene expression: cell to cell signaling
The regulation of the segment polarity genes by the pair-rule genes is only the first
stage of regulation. There are two problems that must be overcome. First, the
expression of the coordinate, gap and pair-rule genes fades away and new
mechanisms for regulating wingless and engrailed are required. Furthermore,
cellularization of the embryo has occurred by this stage and it turns out that the
mechanism for maintaining wingless and engrailed expression is based on cell to cell
communication. This is why not all of the segment-polarity genes are transcription
factors.
How are the patterns of wingless and engrailed maintained?
Genetic experiments showed that en and wg are required for each other's
expression. However, they are expressed in completely different cells, so cell- cell
communication must occur. engrailed encodes a homeodomain protein; wingless
encodes a secreted peptide, a member of the WNT family. Wingless is secreted from
the cells which make it. When the Wingless protein binds to its receptor on posterior
cells, the signal is transduced to the nucleus and maintains the transcription of
engrailed.
A second signal must be invoked to explain the maintenance of wingless expression
by engrailed expression. hedgehog encodes a secreted factor that is responsible for
the signal from the engrailed expressing cells back to the wingless expressing cells.
hedgehog binds to its receptor on the wingless expressing cells and this results in the
maintenance of wingless transcription.
Later in embryogenesis, wingless and engrailed expression become independent of
one another, but the spatial patterns remain the same. So, the control of expression
of the segment polarity genes wingless and engrailed goes through several distinct
phases.