Transcript A-12 Models for gene activation

Gradient-controlled gene activation: cells have to
remember to which concentrations they where exposed
Time
Position
From “The Algorithmic Beauty of Sea Shells” © Hans Meinhardt and Springer - Company
Permanent switch-like gene activation requires
autoregulatory genes
Dimerization for
non-linear
feedback
gene product
The gene product g
The signal m
gene
The signal has an additional activating effect
g
c g2

 g  m
2
t 1   g
Differentiation 6, 117-123 (1976)
Pattern formation based on a communication by diffusion can take place only in very small
fields; communications over longer distances would take too much time. Therefore, patterns
that are formed at small scales should lead permanent changes in the cells, e.g., by a
concentration-dependent activation of genes. If a gene product g has a positive feedback on
the activation of its own gene, a morphogen m can cause a switch-like activation of a gene in a
part of the field. The gene remains active when the signal is no longer available.
Permanent switch-like gene activation requires
autoregulatory genes
Dimerization for
non-linear
feedback
gene product
The gene product g
The signal m
gene
The signal has an additional activating effect
g
c g2

 g  m
2
t 1   g
Differentiation 6, 117-123 (1976)
At low concentrations of the gene product g, the negative term is dominating, The concentration
of g will decline further. At higher g levels, the autoregulatory term exceeds the decay, and the
concentration will increase until the saturation is reached. The morphogen m is assumed to
have an activating influence on the g-production. It can bring the system over the threshold
such that a permanent switch form low to high g occurs. The gene remains activated even after
the morphogen is no longer available.
The autocatalysis required for gene activation can be
realized by a mutual inhibition of two genes
If two genes mutually inhibit each other, they may behave as a switching system.
One gene becomes activated and the other suppressed. Thus, as in pattern
formation, the autoregulation required for a permanent and switch-like gene
activation can result of the from an inhibition of an inhibition….
Figure kindly supplied by Denise Montell,
see Starz-Gaiano et al. (2008).
Dev. Cell 14,726-738
A recently discovered example is the formation of the border cells next to the polar
cells in Drosophila oocyte development. These border cells (red) are responsible
for the departure of the pole cells (green) and their movement towards the proper
oocyte. For this function an all-or nothing decision is crucial…
A step-by-step explanation how the switch-like
JAK/STAT activation works:
1. Pole cell (green) produce a diffusible signal, UPT
(grey)
2. UPT induces a transcription factor, STAT (red);
STAT has initially the same distribution as UPT
3. STAT induces APT; APT represses STAT. With
this alone, STAT would remain low. However,…
4. …STAT induces at high levels SLBO (black)
5. SLBO and APT inhibit each other and SLOBO
inhibits the action of APT on STAT
Result: at high STAT levels, the action of APT is
suppressed by SLOBO; STAT is high
Further away, STAT is very low
… now the total time course…
This time course corresponds rather precisely to the observations. Also
mutants or patterns after ectopic gene expressions are well described.
Note that there is an unusual behavior: cells that are exposed to a low
morphogen concentration become de-activated. In contrast, in usual
gene activation systems, the cells only become activated if the
concentration is above a threshold (see above).
(see Starz-Gaiano et al. (2008). Feedback Inhibition of JAK/STAT signaling by apontic is required to limit an invasive
cell population. Dev. Cell 14,726-738. A GUIDED TOUR is available in the program sp [GT129b]
Space-dependent activation of several genes
by a morphogen gradient
Gene 4
J. theor. Biol. 74,307-321, 1978
Models of biological pattern formation, 1982
Gene 1
According to the classical view, a graded distribution can activate several genes in a
concentration-dependent fashion. The problem: how can a minute concentration difference in
adjacent cells be decisive which gene becomes activated?
Model: the cells become sequentially promoted. If the concentration is high enough, the next
gene will become active; the previously active gene could be suppressed. Like a barrel that
is lifted up by a flood: the highest level is decisive on which level the barrel comes to rest. A
later higher flood can lift up the barrel further, a second lower flood is without influence. In
other words, the cells measure the highest level they were exposed to.
Gene activation: step-wise irreversible promotion
gi ci gi 2  bi gi 1 m

 ri gi
n
t
2
c
g
i i
i 1
Gene 4
Gene 1
This equation is easy to read: each gene has an autocatalytic
feedback on its own activation. All the alternative genes i, i =
1…. n compete with each other (sum-term in the denominator).
The morphogen m has an activating influence and may initiate
the positive loop if its concentration is sufficient. The
mechanism was designed in such a way that activation of each
further gene requires a higher concentration of m.
J. theor. Biol. 74, 307-321. (1978)
A problem that was to be solved: the genes least sensitive for the signal, i.e., genes that
require the highest morphogen concentration for activation (gene 4 in the example) must
be able to dominate over the genes that are more sensitive. How can an insensitive gene
win the competition?
Proposed solution: genes that are less sensitive for the morphogen are better in the
autoregulation. In the equation above, this requires with ci+1 > ci ; i = gene number. This
condition leads, in addition, to the property that each further step requires a higher signal
concentration. Although the signal is smoothly graded, there is an all-or-nothing response
in the activation of the particular genes.
Upon a later increase in the morphogen concentration, a
corresponding shift in the regions of gene expression occurs….
In contrast, after a lowering of the morphogen concentration, the regions of
expression remains unchanged; the „promotion“ is irreversible and the cells cannot
fall back. This corresponds to the well-known posterior or distal transformation.
Irreversible and unidirectional “promotion”
A cell transplanted from a region of low signal
concentration into a region of high signal
concentration will switch from gene 1 (blue) to gene
4 (brown).
Other way round, a cell in which gene 4 is active will
not change the gene activity after transplantation
into a region of low signal concentration.
This unidirectionality corresponds to the posterior
or distal transformation.
For examples see: Udolf, et al., (1995). Science 269, 1278-1281; Gomez-Skarmeta, et al., (2003) Nature Rev. Neurosci. 4,587-598;
Grapin-Botton, et al., (1998) Development 125,1173-1181
Problem: if promotion starts too early,
anterior structures will be lost…
Early in development the cells that should see a low concentration could be too
close to the source or the system needs some time until the final low level
equilibrated: an too early irreversible promotion would lead to a loss of anterior
structures, as shown in the simulation above ….
Solution: delay of gene activation by signal
antagonists
This problem can be solved by a delay of the step-wise promotion. In Xenopus, for instance,
the early anterior-posterior determination of the brain is under the control of a WNT-gradient.
However, under maternal control, the early embryo is full of WNT antagonists (such as dkk;
blue in the simulation). This leads to a delay in the posterior transformation until the
maternally supplied antagonist is gone. In this period, regions of low morphogen levels are
established and all genes become activated at their correct position.
Due to irreversible promotion: a shortranging signal can organize a larger field
4
3
2
1
Position
If cell proliferation is essentially restricted to the source region, a short-ranging gradient
can control a larger region. Cells leaving the source region due to proliferation enter a
region of lower signal strength and attain, therefore, a stable determination. In contrast, in
the source region, the promotion can proceed further. Evidence for such a mechanism
exists for the determination of the digits in the chicken wing bud [Harfe et al. (2004). Cell 118, 517] .
Conclusions:
The selection of a particular pathway requires the activation of a particular gene
and the suppression of the alternative genes. With gene products that have a
positive feedback on the activation of their own gene combined with the
repression of the alternative genes, the cell has to make an unequivocal choice:
only one of the genes that could be activated at a particular stage can become
active.
Gene activation and pattern formation in space share formal analogies. The
long-range inhibition in spatial pattern formation corresponds to the repression of
the alternative genes in gene activation.
Thus, essential steps in development can be regarded as a sequence of patternforming processes in real space coupled with a pattern formation among
alternative genes.