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Summary BBS2002: From cradle to grave
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BBS2002: FromCradle to Grave
CASES
Case 1: Neural development…………………………………2
Case 2: Lung development.....................................20
Case 3: bone development………………………….………38
Case 4: muscle development……………………………...54
Case 5: Hormonal changes and puberty……………....69
Case 7: Functional decline……………………………………84
Case 8: Mitochondrial and aging………………………….94
Case 9: Hallmarks of aging………………………………….107
Case 10: Hallmarks of cancer……………………………..123
Case 11: COPD…………………………………………….……..145
Case 12: Alzheimer’s………………………………………….156
,CASE 1: NEURAL DEVELOPMENT
Learning goals:
LG1: Revision of development in the embryonic/fetal stage (neurulation, changes in
structure, signaling)
LG2: Explain the brain cell formation (proliferation, migration, differentiation; notch
signaling)
LG3: How does neurotrophic signaling work and why?
LG4: How are synapses formed? (compare central and peripheral synapses)
LG5: How does synaptic plasticity develop? (long-term potentiation/depression)
LG6: What is the timeline of development of brain structures? (Explain the stages in Fig.4)
LG7: How is damage to the nervous system repaired? (Compare central and peripheral NS)
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,LG1: REVISION OF DEVELOPMENT IN THE EMBRYONIC/FETAL STAGE (NEURULATION,
CHANGES IN STRUCTURE, SIGNALING)
Neurulation
First stage: induction
At the beginning of the 3rd week of embryonic development, the induction of neurulation
begins. The notochord and paraxial mesoderm secrete signaling molecules, resulting in the
differentiation of the overlying ectoderm into neurectoderm.
Second stage: formation of the neural plate
The neural plate originates from the neuroectoderm, an area with compressed and
increased epithelial cells. It begins at the cranial end and grows toward the caudal. The
cranial end initially increases rapidly in size and is, therefore, wider than the caudal end.
Third stage: Formation of the neural tube
On approximately the 18th day of embryonic development, the neural plate deepens and
forms the neural groove. Its margins are increased by the so-called convergent extension.
This means that the cell rows shift into one another and form the neural folds. The neural
folds then merge, cut off the neural groove, and form the neural tube. This is the basis for
the central nervous system.
2
,Stage 4: Closing of the front and rear neuropore
The neural tube resembles a channel that is open at both ends. The end of the head is called
the anterior neuropore. The brain will develop in this region. The caudal end, the posterior
neuropore, will form the spinal cord. The cavity of the neural tube later forms the
ventricular system of the central nervous system.
On the 25th day of embryonic development, the end of the head joins the anterior
neuropore. Two days later, the posterior neuropore closes. The neural tube now ends
approximately at the height of the later S2 segment. If the closing of the neural tube is
disturbed, the neural tube defects or dysraphic disorders can occur.
Stage 5: Cells of the neural crest
The neural crest separate at the closed neural folds. The cells of the neural crest are very
important in embryonic development. These cells have the ability to move around and
diversify into numerous cell types. They form the glial and nerve cells, melanocytes of the
3
,skin, calcitonin cells of the thyroid gland, cells of the adrenal medulla, and many of the
connective tissue cells and bone cells of the skull.
Primary versus secondary neurulation
Primary neurulation refers to the development of the neural tube under the influence of the
notochord and the mesoderm. It ends in the 4th week of embryonic development with the
closure of the posterior neuropore. This is followed by secondary neurulation. The caudal
end of the neural tube then develops into the neural notochord and is canalized. This
process ends in the 6th week,.
Formation of the vesicles
As the anterior end of the neural tube starts to develop into the brain, it undergoes a couple
of enlargements; the result is the production of sac-like vesicles. Three vesicles form at the
first stage, which are called the primary vesicles. Those are called the prosencephalon
(forward-most vesicle, forebrain), the mesencephalon (midbrain) and the rhombencephalon
(hindbrain).
The brain continues to develop, and the vesicles differentiate further. The three primary
vesicles become five secondary vesicles. The prosencephalon enlarges into the
telencephalon and the diencephalon. The telencephalon will become the cerebrum. The
diencephalon gives rise to structures like the thalamus and hypothalamus. The
mesencephalon does not differentiate further. The midbrain is an established region of the
brain at the primary vesicle stage of development and remains that way. The
rhombencephalon develops into the metencephalon and myelencephalon. The
metencephalon corresponds to the adult structure known as the pons and also gives rise to
the cerebellum. The myelencephalon becomes the medulla oblongata.
4
,LG2: EXPLAIN THE BRAIN CELL FORMATION (PROLIFERATION, MIGRATION,
DIFFERENTIATION; NOTCH SIGNALING)
Neuronal development
There are three stages recognized in the process of neuron development and the formation
of the nervous system.
Neurogenesis
Cells that have yet to be differentiated will undergo mitosis to produce either stem cells, or
neuroblasts, which will ultimately be differentiated into many different types of neurons.
The difference between neuroblasts and stem cells is that neuroblasts are mostly involved in
embryonic development and stem cells are more present in adult neurogenesis. These cells
continue dividing and eventually form the ventricular zone, this leads to the formation of
three separate zones: ventricular zone, intermediate zone and marginal zone.
Step 1: Cell proliferation
At early stages of embryonic development most progenitor cells in the ventricular zone of
the neural tube proliferate rapidly. Many of these early neural progenitors have the
properties of stem cells: they can generate additional copies of themselves, a process called
self-renewal, and also give rise to differentiated neurons and glial cells. As with other types
of stem cells, neural progenitor cells undergo stereotyped programs of cell division.
One mode of cell division is asymmetric: The progenitor produces one differentiated
daughter and another daughter that retains its stem cell-like properties. This mode does not
permit amplification of the stem cell population. In a second mode neural stem cells divide
symmetrically to produce two stem cells, and in this way expand the population of
proliferative progenitor cells. The incidence of symmetric and asymmetric is influenced by
signals in the local environment of the dividing cell, making it possible to control the
probability of self-renewal or differentiation.
5
,Step 2: Cell migration
In this stage, cells that were previously responsible for creating the ventricular zone now
must move great distances to establish distinct cell populations for further embryonic
development. These migrations are genetically pre-determined and so are not random in
any way.
The formation of the ventricular, intermediate and marginal zone is due to the movement
of cells. Cells in the intermediate zone have already begun developing into neural and glial
cells.
What constitutes cell migration is the movement of more cells (which are being formed
during the ongoing process of neurogenesis) along the radial glia toward the marginal zone
from the ventricular zone. Once they reach the marginal zone, they begin differentiation.
6
,The first cells to migrate to the cortical plate are those that form the subplate. As these
differentiate into neurons, the neural precursor cells destined to become layer VI cells
migrate past and collect in the cortical plate. This process repeats again and again until all
layers of the cortex have differentiated. The subplate neurons then disappear.
7
,Stage 3: differentiation
Now, the process of differentiation is different from normal cell mitosis in that the embryo’s
DNA dictates the nerve cells’ specific physiology for their future core functions. Here is
where it is determined what type of nerve cell they will become. Notch signaling has several
roles in cell differentiation in the developing cerebral cortex. The activation of Notch
signaling in glial progenitor cells result in the differentiation as astrocytes and inhibits
differentiation as oligodendrocytes. Notch signaling also inhibits progenitor cells from
differentiating into neurons.
Stage 4: outgrowth
In this stage, the foundational cells of the nervous system truly begin to take the shape we
all know. Here is where the axons and dendrites begin to form – differentiation continues
through this stage to direct these developments, as each neuron requires a distinct
physicality based on their ultimate function.
LG3: HOW DOES NEUROTROPHIC SIGNALING WORK AND WHY?
What are neurotrophins?
Neurotrophins are a family of proteins that play an essential role in the survival,
development and function of neurons. They significantly regulate axonal and dendritic
growth and guidance, synaptic structures and connections, neurotransmitter release, long-
term potentiation (LTP) and synaptic plasticity. Neurotrophins prevent the associated
neurons from initiating programmed cell death, which allows the neurons to survive. They
also induce the differentiation from progenitor cells to form neurons. Neurotrophins are
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, initially synthesized as precursor or preneurotrophins which are cleaved to produce the
mature proteins. Pro-neurotrophins are cleaved intracellularly by FURIN.
There are four types of neurotrophins in mammals in total:
- Nerve growth factor (NGF)
- Brain-derived neurotrophic factor (BDNF)
- Neurotrophin-3 (NT-3)
- Neurotrophin-4 (NT-4)
Factor Function Mechanism
Nerve growth factor (NGF) critical for the survival and NGF binds and activates
maintenance of sympathetic receptor TrkA on the
and sensory neurons. neuron.
Brain-derived neurotrophic Supporting the survival of
factor (BDNF) existing neurons and
contributes to the growth
and differentiation of new
neurons, stimulates
neurogenesis
Neurotrophin-3 (NT-3) Similar functions as BDNF’s Able to activate two of the
and act on certain neurons receptor tyrosine kinase
of the peripheral and central neurotrophin receptors
nervous system (TrkC and TrkB)
Neurotrophin-4 (NT-4) Mainly binds to TrkB
tyrosine receptor kinase
Neurotrophic factor hypothesis
The decision of a cell to live or die is determined by the competition for survival-promoting
signals such as neurotrophic factors. A complex cascade of receptor-mediated intracellular
signaling events results in the activation of anti-apoptotic (cell-survival) or pro-apoptotic (cell
death) genes.
Neurotrophins act at specific cell surface receptors. Most of the receptors are neurotrophin-
activated protein kinases (trk receptors). They phosphorylate tyrosine residues on their
substrate proteins. This phosphorylation reaction stimulates a second messenger cascade
that alters gene expression in the cell’s nucleus.
So neurotrophins save the cell from self-destruction by turning of the genes that cause
apoptosis.
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