92
6 Cells United
the topology of the expression domain. Adding more initiating links with different
thresholds may increase the number of subdivisions, but domain shapes will always
be set by the signal level sets, making it difficult to explain less regular gene expression patterns, such us cusp-like or eyebrow-shaped groups of cells in the eggshell.
Patterning becomes more variegated if external (paracrine) signals are complemented by autocrine morphogenetic signaling initiated within the embryonic tissue by proteins whose expression is in turn determined by local morphogen levels.
Christiane N¨ usslein-Volhard (2006), elaborating upon her discovery of the first morphogen, showed how the various autocrine signals determine finer patterning details,
like the bands on Drosophila, which, even though repetitive, do not in any way follow Turing’s recipe for creating periodic patterns, but are created one by one by
local signals.
I tried to develop the picture of two-dimensional patterning enhanced by autocrine signaling in a generalized way (Pismen and Simakov, 2011). If there is a
single target gene and a single autocrine signal, there are altogether sixteen combinations of their expression in the presence or absence of the autocrine signal. The
number of combinations grows exponentially as 2 2(n+1) with the number n of autocrine morphogens, leading to a great variety of expression domains for the same
intrinsic genetic scheme. The diffusional range of the autocrine signal is typically
shorter than that of externally supplied morphogens, and if it is expressed in one
domain of the “Franco-German flag” it can affect expression of the target in neighboring domains. Thus, expression in the blackened area in the left-hand panel of
Fig. 6.8 will be affected by the autocrine signal initiated in the central square. This
helps to explain gene expression in domains of convoluted form.
This abstract work was prompted by cooperation with real biologists in a project
generously funded by the Human Frontier Science Program. My younger colleague
made a brilliant career move from a PhD on the theory of catalytic patterns to experiments with the Drosophila fruit fly, which, after serving to fine-tune the laws of
heredity, has become the most important “model animal” for development studies.
A particular question to be solved was positioning of a narrow and skewed eggshell
domain initiating the formation of dorsal appendages. Even experimentalists with
a solid theoretical background have trouble with riddles about the inner life of the
Drosophila fly, and the conjectured signaling and expression scheme kept changing
from week to a week. Eventually, we came to a reasonable development scheme
including autocrine signaling with the sought-for geometry (Simakov et al, 2012),
evolving as sketched in Fig. 6.8. For my part, I couldn’t care less about dorsal appendages, so I let my iMac, armed with Wolfram’s Mathematica, generate random
expression schemes with feed-forward motifs leading to a great variety of patterns,
with the computer itself selecting those with a non-trivial geometry for my attention.
My theory was a flop: the leading paper (Pismen and Simakov, 2011) was never understood nor cited. In our day, researchers are interested in particular details rather
than in abstract schemes, and they are surely right. The signaling pathways of development are more variegated than a theorist could ever imagine.
The scaling and robustness problem is an Achilles heel of expression patterns
organized by morphogenetic gradients, and it is not helped at all by adding more
6 Cells United
the topology of the expression domain. Adding more initiating links with different
thresholds may increase the number of subdivisions, but domain shapes will always
be set by the signal level sets, making it difficult to explain less regular gene expression patterns, such us cusp-like or eyebrow-shaped groups of cells in the eggshell.
Patterning becomes more variegated if external (paracrine) signals are complemented by autocrine morphogenetic signaling initiated within the embryonic tissue by proteins whose expression is in turn determined by local morphogen levels.
Christiane N¨ usslein-Volhard (2006), elaborating upon her discovery of the first morphogen, showed how the various autocrine signals determine finer patterning details,
like the bands on Drosophila, which, even though repetitive, do not in any way follow Turing’s recipe for creating periodic patterns, but are created one by one by
local signals.
I tried to develop the picture of two-dimensional patterning enhanced by autocrine signaling in a generalized way (Pismen and Simakov, 2011). If there is a
single target gene and a single autocrine signal, there are altogether sixteen combinations of their expression in the presence or absence of the autocrine signal. The
number of combinations grows exponentially as 2 2(n+1) with the number n of autocrine morphogens, leading to a great variety of expression domains for the same
intrinsic genetic scheme. The diffusional range of the autocrine signal is typically
shorter than that of externally supplied morphogens, and if it is expressed in one
domain of the “Franco-German flag” it can affect expression of the target in neighboring domains. Thus, expression in the blackened area in the left-hand panel of
Fig. 6.8 will be affected by the autocrine signal initiated in the central square. This
helps to explain gene expression in domains of convoluted form.
This abstract work was prompted by cooperation with real biologists in a project
generously funded by the Human Frontier Science Program. My younger colleague
made a brilliant career move from a PhD on the theory of catalytic patterns to experiments with the Drosophila fruit fly, which, after serving to fine-tune the laws of
heredity, has become the most important “model animal” for development studies.
A particular question to be solved was positioning of a narrow and skewed eggshell
domain initiating the formation of dorsal appendages. Even experimentalists with
a solid theoretical background have trouble with riddles about the inner life of the
Drosophila fly, and the conjectured signaling and expression scheme kept changing
from week to a week. Eventually, we came to a reasonable development scheme
including autocrine signaling with the sought-for geometry (Simakov et al, 2012),
evolving as sketched in Fig. 6.8. For my part, I couldn’t care less about dorsal appendages, so I let my iMac, armed with Wolfram’s Mathematica, generate random
expression schemes with feed-forward motifs leading to a great variety of patterns,
with the computer itself selecting those with a non-trivial geometry for my attention.
My theory was a flop: the leading paper (Pismen and Simakov, 2011) was never understood nor cited. In our day, researchers are interested in particular details rather
than in abstract schemes, and they are surely right. The signaling pathways of development are more variegated than a theorist could ever imagine.
The scaling and robustness problem is an Achilles heel of expression patterns
organized by morphogenetic gradients, and it is not helped at all by adding more