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Cell signalling in development: Notch signalling and establishment of the embryonic body plan £7.49
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Cell signalling in development: Notch signalling and establishment of the embryonic body plan

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Cell signalling in development: Notch signalling and establishment of the embryonic body plan

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  • February 18, 2021
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  • 2020/2021
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torchiatantoine
And my third story about how NOTCH helps build the vertebrate body plan. So in the last set of talks,
we were focused on the role of notch in neurodermal progenitors and then the role of notch in one
of those derivatives, namely the neural tube. Now we're going to look at the role of notch in the
other neurodermal progenitros derivative, and that is the skeleton. So here we have a number of
vertebrate species, and what you will see is that the final adult body plan of these vertebrate species
is very different. However, they share a number of conserved features and one of those is apparent
on the next slide.

And that is that they all have a segmented body axis, which is most definitely seen in the formation
of this skeleton. Again, the final product looks very different, but all of these skeletons are made up
of a repeated series of segments or bones. Now, this process actually begins very early in
development, and that's what's represented on this slide that I've shown you before. And so here
we're looking at a chicken embryo after just one and a half days of development and a human
embryo after four weeks of development. And already at these very early stages, you can see the
appearance of these segments. Either side of the developing neural tube and those segments will go
on to form the skeleton.

And this is a very important structure because, of course, it offers both flexibility as well as rigidity.

And so without the skeleton, we would not be able to hold ourselves upright. So this is an essential
part of body plan formation. It's very important as well to understand this process, because it's a
huge number of congenital vertebral malformations that lead to a very lower quality of life for the
patients. However, in many of those situations, we don't know the etiology, the underlying gene
aberration. They're fairly prevalent because they occur in one in every thousand humans.

And we're going to focus on one particular set of those diseases called spondylocostal dysostosis
(SCD). And this affects the segmentation of multiple vertebrae. Patients suffering from this disease
suffer respiratory problems due to volume restricted thoraces, and 50 percent of those cases die in
infancy. So in one of these forms of congenital vertebral malformations, which we call spondylocostal
dysostosis linkage analysis has shown that there are this comes about through mutation in a number
of genes. And what's really interesting is that all of these genes, so DLL3, MESP2, LFNG and HES7 are
all related to that notch pathway. So that suggests that Notch may be playing a crucial role in this
process, but these are very late stages in the adult debate earlier on. So we did some experiments in
which we cultured chicken or mice embryos in the complete absence of notch signaling. So on the
top here, we're looking at mouse embryo and then here we're looking at a chicken embryo. And
what you can see in the control on the side view is some beautifully formed segments marked by the
expression of this gene Uncx4.1. And then down here, we've got dorsal view of the chicken embryo,
the wild type. And again, we can see this beautiful segmented expression profile of Uncx4.1, which
expressed in the posterior half of every somite. On the right hand side of those panels, what you can
see is either a mouse embryo that completely lacks both Psen1 and Psen2 which, if you remember
from the last set of slides, are the two main components that are required for the gamma secretase
cleavage of notch to form activated NICD.

And then down here, we've got a chicken embryo cultured in the presence of DAPT, which again is a
pharmacological inhibitor of that gamma secretase activity. So chicken or mice embryos cultured in
the absence of gamma secretase activity. So in the absence of formation of NICD, completely lack all
segments, suggesting that Notch is essential for so much information in mouse and chick. So let's
learn a little bit more about how this process comes about in order to be able to understand where
notch is playing a role. So, as I said, at two days of development in the chick, there's already clear

, signs of we look at this blow up my photograph of that same embryo, we can see that there are
three pairs of segments at the top, three pairs of somites, and they lie just anterior to this
unsegmented region of presomitic mesoderm . OK, so two rods of unsegmented presomitic
mesoderm that that lie adjacent either side of this neural tube. And what happens is that this
presomitic mesoderm becomes progressively segmented according to a strict periodicity, that
species specific. So a new pair of somites is segmented off the top end of that tissue with a strict
periodicity. And these somites if to took a cross section through this tissue and looked inside, what
you would see is the developing neural tube, which we spoke about last time, the notochord and
then these two somites.

How does this presomitic mesoderm form, and what are the processes involved in somite formation
from that presomitic mesoderm well system, as I said, is progressive. So if we consider ourselves to
be a little cell population here in the tail end of that presomitic mesoderm . Then the position of
those cells gradually becomes more anteriorly displaced as a result of two other processes. One is
that you get continual production of new presomitic mesoderm cells , at the caudal tail end of the
embryo. And at the same time, what happens is you get progressive segmentation of new somite
pair at the top end of this tissue, and we just see that in the next schematic. So new cells are coming
in. A new segments are forming at the top end. So is this is becoming segmented down, a new cells
are forming behind this little red blob of cells, then the relative position of that cell group becomes
more and more anteriorly displaced until that group of cells is itself segmented into a somite pair.

So, as I said, the periodicity with which somite form from the top end of this presomitic mesoderm
is species specific. So a new pair of somites buds off from the top end of that tissue every 30 minutes
in fish, every 90 minutes in chick, every two hours in the mouth and every eight hours in the human.
So that gave rise to the idea that there was some kind of developmental clock acting in this
presomitic mesoderm telling those cells when to segment. And the first experimental evidence to
support those theoretical models came about through the analysis of the mRNA expression of this
gene called cHairy1, which is a Notch target. So when we look at the mRNA expression of this gene in
a group of embryos such as these, which all have the same developmental age, we know that
because they have the same number of somites, then what we can find is some embryos that have
this very broad caudal expression in the tail end of that tissue, whereas other embryos have a much
narrower expression profile at the top end of the anterior and the presomitic mesoderm. the
experimentalists that were studying this were able to show that these different profiles occur in this
static form that we're looking at here, because in actual fact, this expression profile is very dynamic.
So this gene is initially expressed indeed in a broad caudal domain. But that expression domain
narrows while moving anteriorly such that it eventually becomes restricted to just a very narrow strip
at the top end of that tissue and then a new wave of expression begins again caudaly. But what was
quite striking was that the experimentalists were able to show that the time it takes for a wave of
transcription to sweep across this tissue was 90 minutes in the chick.

And that is, of course, the same time it takes for a new pair of somites to form. So during that cycle
of expression, what that means is that cells down here or initially expressing the gene, but that they
then turn off the expression of the gene for the rest of the cycle. In contrast, these cells up here are
not expressing the gene initially at the onset of that cycle, and then they turn expression on. So sure
enough, this gave experimental evidence for that being a dynamic pulsatile periodic expression of
these so-called clock genes in the presomitic mesoderm that we believe are setting the timing, the
tempo of segmentation. And we can see that in a dynamic fashion by looking here at this little movie
on the right. This schematic movie, which is trying to recapitulate what that dynamic gene expression
would look like in this segmented tissue InVivo. So what it is, is you have a wave of expression that

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