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Complete summary of all lectures of the molecular principles of development course
- Instelling
- Radboud Universiteit Nijmegen (RU)
All lectures summarized into detail including experimental evidence given during the lectures.
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Summary molecular principles ofdevelopment
Lecture 1 – Intro and basic concepts – 07/11/2019
Forward genetics → there are random mutations and there needs to be a screening of the
corresponding phenotypes. Interesting phenotypes are investigated.
Reverse genetics → make mutations in a gene of interest and then analyze the corresponding
phenotype.
Lewis and Volhard → discovered lots of genes involved in patterning of Drosphilia.
Gap genes, pair rule genes and segment polarity genes
allow the embryo to be segmented.
• Gap genes → the loss of gap genes result in a
reduced number of segmnts as shown in the embryo on the
right.
• Pair rule genes → the loss of a pair rule gene (e.g.
even skipped) allows only odd numbered segments to
develop.
• Segment polarity genes → loss of a segment polarity
gene leads to segments with similar head and tail ends.
Hox genes → occur in flies, but also in mice → also important for patterning.
• Expression along the anterior-posterior (A-P) axis relates to the genomic position and the
timing of the expression.
Drosophila
Life cycle: fertilized egg → cleavage (creates a syncytial blastoderm) → gastrulation → hatching →
larvous stages occur → hatch into an adult fly. The whole life cycle only takes 9 days.
Flies have a specific place where the sperm
enters, which is the micropyle and is anterior.
At the opposite site of the sperm entry is
where the gametes will form. This means the
cell already has polarity. This is not true in all
species. What then happens is that the nuclei
divide, but the cells don’t. That is called a
syncytium (a big bag of cytoplasm containing
multiple nuclei). There is nuclear devision
without cytokinesis. First the nuclei stay in
the center, then they move to the periphery. When the nuclei are in the periphery and they have no
cellular membranes, the cell is called a syncytial blastoderm. Whenever they have moved to the
periphery, they will form cellular membranes around them. When the cellular membranes are
formed there is a cellular blastoderm. In the syncytial blastoderm there are pole cells present which
will give rise to the germ layer with the germ cells.
If there is a syncytium, molecules can freely diffuse. There will be a local source and molecules will
diffuse. What diffusion will do whenever there is a local source is that concentrations of molecules
will not be the same everywhere. This is what is happening in the drosophila embryo quite a bit.
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,Gastrulation is the major morphogenetic proces of development. It turns organisms from a ball of
cells to organisms with polarity and axes. Obvious morphological segmentation is being made during
gastrulation.
In Drosophila the egg already has polarity, which in Drosophila corresponds to the anterior-posterior
axes already. It also already has dorso-ventral polarity. This is not true for the vertebrates. However
the zebrafish and the Xenopus have a different kind of polarity which does not yet correspond to a
normal body axes, wheras mammalians at this point have no polarity at all.
In zebrafish there is a syncytium, which is the yolk. This because the zebrafish has meroblastic
division, which means that devision does not go through the whole egg, but only happens on top.
This is different in Xenopus and mice, which have holoblastic devision, which means that cleavage
happens right through the middle of the egg.
Patterning → how does a cell know where it is? Molecular signals make cells in a certain region
respond differently than cells in other regions.
Definition patterning → the process of establishing positional information at the molecular level
among similar cells. This has everything to do with forming bodyaxes.
• Dorsal-Ventral axis → belly and back.
• Anterior-Posterior → nose and tail.
• Medial-Lateral → left and right.
All these body axes start by creating polarity and thus breaking the symmetry. The oocyte in
mammals is radiallt symmetrical. If there are no body axes formed in mammels, we would all be a
ball of cells. At a certain point the symmetry is broken. This can be done in many ways, but the most
famous way is that whenever cells divide, they will inherit different molecules or different
concentrations of molecules and then become different. Another way is by molecular gradients →
here there is a local source somewhere and then there is a diffusion (this can by in a syncytium or in
interstitional space). Depending on the concentration of the molecule cells respond in a certain way.
• Patterning is not the same as differential gene expression. Patterning happens way earlier
than gene expression processes. Patterning will lead to different gene expression, but it is
not the same.
Bicoid → inhibits the translation of a mRNA that encodes the caudal protein. Therefore caudal is only
expressed in the anterior part, not in the posterior part. These are often maternal genes (genes that
are expressed in the oocyte that produce RNA, so this RNA is already present in the oocyte before
fertilization). A lot of these maternal genes are expressed in gradients in the embryo. When the
oocyte starts to transcribe its own genes (half of which from the mother and half from the father), it
starts to respond to the activities of the maternal proteins. This process has increased specificity and
precision.
• Therefore, the concentration of bicoid and caudal can tell you exactly where you are in the
embryo.
Along the sime line of Drosophila genes → expression is more specific.
• Maternal and gap genes together for example produces the stripe pattern seen in pair rule
genes.
Cells know what they should become even before the slightest morphological difference is seen.
Germ layer → ectoderm mesoderm and endoderm → is different from the word germ line.
Germ line → produces the cells for reproduction.
2
, Every form of life, except the
sponges, has three different germ
layers.
Fate, specified and determined are
not the same.
• Fate → we will know what
the cells (most likely) will give
rise to, but the cells do not.
• Specified → cells know what
they wll be, but they can
change their mind whenever
they are exprosed to a
different environment.
Molecular signals have
already been received.
• Determined → cells know
what they will be and will
proceed no matter what.
Fate mapping experiments → you inject fluorescent dye in a single blastomere. Then they watch
where these cells will end up. It is traceable what the cells will give rise to.
Fate maps → will tell you what most likely the cell will contribute to. The cell itself does not know yet
what it will become.
In situ hybridization → technique that makes it able to look at gene expression patterns.
How do you know you have reached saturation (all genes identified) in a forward genetics screen →
most genes that you find, you find more than once.
3
, Lecture 2 – Axes and germlayers I – 09/11/2019
Zygote → the just fertilized egg. This is before it is called an embryo.
Maternal to zygotic transition
In the first few cleavages, the embryo does not grow.
The cells just become smaller within the space they
were in before. The size of the oocyte is variable
between species. As the oocyte is the biggest cell of
the body, it provides a lot of goodies. This contribution
varies between species. The significance of this
contribution is that the early stages are mainly driven
by maternal gene products. RNAs but also proteins
that are translated from maternally stored RNA which
are present in the oocyte are used by the zygote. How
it is deplaced in time varies between species. The red
zones in the picture are the maternal mRNA and the
light and dark blue zones is new transcription. The
overal rule between these species is that the earliest
cleavage devisions or the first stage after fertilization
the embryonic genome is not transcriptionally acive. This means that the embryo does not yet
transcibe its own genes. Embryonic development at this stage depends entirely on maternal
products. After a while (it differs between species when this is) there is a first phase during which the
genes of the embryo itself are being transcribed. With the transcription of its own genes the embryo
starts to take control of its own genetic program. This is called the maternal to zygotic transition
(MZT). Here, the maternal RNA degenerates and there is zygotic genome activation (ZGA). This is the
light blue zone in the picture. In externally developing species (flies, fish and frogs), this phase is also
called the mid-blastula transition (MBT). In this phase, there is new embryonic transcription, loss of
cell cycle synchrony and cells become more motile (needed for gastrulation).
There are models that describe how the mid-blastula
transition is regulated. This model states that at a certain
point there is at a certain moment a repressor of
transcription. This actually is a repressor of the events of
the mid-blastula transition. There is a constant amount
of repressor. What happenes as development starts is
that the embryo starts to make its own DNA. With every
cleavage devision there is a twofold increase in the amount of DNA that is produced by the embryo.
If the repressor has something to do with DNA, there will be a dramatic change in the ratio of
cytoplasm to DNA or in the amount of repressor to DNA. If you say there is a threshold and you dilute
the repressor enough (as it is spread over many cells), the repressor will become less affective and
then the zygotic genome kidn of awakens and can start being transcribed. There are several
experiments that came to this model:
• A partial constriction experiment → the egg was squeezed. The normally round egg is now
almost pinched into two different parts, but you don’t do this completely. There is still a
small connection between the two halves. After fertilization the pronuclei fuse and they sit
either on one end or on the other end. This means that one halve of the partially restricted
embryo has the nucleus and the other part hasn’t. The nucleus will be dividing and the cells
will become smaller and smaller. Eventually one of these nuclei is close to the opening and
small enough to be able to pass through it. This one nucleus on the other side will be
confronted with this large bag of cytoplasm and will start to divide there as well. Now the
nucleus to cytoplasm ratio is different between the two halves. If you look at what happens
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