lecture 18 development: building a nervous system Flashcards
what does the brain begin as
the product of a single cell, the fertilized zygote
why study development of nervous system
1) demystify adult brain by following formation
2) learn about what causes missteps in brain development
3) turning on developmental mechanisms in later life could hold the key to curing many brain disorders
4) plasticity in babies can hold additional potential for human mind to learn better
parts of neural development
generate components
hard wiring
activity dependent tuning
what is step 1 of neural development and what happens in it
neurulation: begins once the 3rd germ later (mesoderm) is created between the ectoderm (outer) and endoderm (inner) layers
these 3 germ layers make up all the tissues of the body
embryology
studying how an embryo grows from egg cell to adult
embryology with frog
vegetal pole
splits in half
becomes many different cells called blastula
gastrulation (pregenitor stage before nervous system starts)
blastopore (little pore created for intestinal system)
ectoderm and endodorm, mesodorm between
neurula, then nervous system
then free swimming tadpole
when does the nervous system begin its development (neurulation)
after the gut is hollowed out starting from the blastopore (gastrulation)
is human development faster, slower, or at the same pace as a xenopus frog
much slower (human neurulation occurs at 17 and 28 days after fertilization, frog neurulation occurs at 13-17 hours)
three primary germ layers
endoderm
mesoderm
ectoderm
endoderm (1st germ layer in neurulation)
gives rise to gastrointestinal tract, organs like liver and pancreas
mesoderm (2nd germ layer in neurulation)
gives rise to muscles, bones, and a small structure that ends up in the vertebrae called notochord
ectoderm (3rd primary germ layer in neurulation)
gives rise to skin and the nervous system via the neural plate
what does neural tube become
central nervous system
what does neural crest become
peripheral nervous system
organizer experiment
hilde mangold and hans spemann
The dorsal lip of the blastopore now called “the organizer” normally gives rise to the mesodermal notochord, beneath the neural tube.
Spemann and Mangold
transplanted the dorsal lip of the blastopore from one
embryo into another (giving the recipient embryo a second organizer) at a site far from the original blastopore. The amazing result: It INDUCED a whole second body axis, including the neural tube
what is step 2 of neural development and what happens in it
regionalization
segmentation and segmental identity
key concept: positional information
key concept of regionalization: positional information
Studies of early embryonic development led to the concept that the position of a cell in an animal determines the identity it will acquire.
A chemical (“morphogen”) released from one end of a body axis in the embryo
forms a gradient, and the concentration of morphogen determines which genes
are activated. The pattern of gene expression, in turn, endows the cell (or tissue) with specific features.
regionalization: dorsal ventral patterning
Morphogens that pattern the doral-ventral axis
include “sonic hedgehog” released from the
notochord at the ventral end of the spinal cord.
Others are released from the dorsal end.
(from ventral highest concentration to dorsal lowest concentration)
Different types of neurons at
different distances from the
notochord
V1 interneurons
V2 interneurons
MN motor neurons
FP floor plate cells
regionalization: dorsal ventral patterning (hindbrain)
“Cranial” nerves (with Roman
numerals) each with distinct
functions originate from different ”rhombomere”
segments of the hindbrain.
They are differentiated by
transcription factors (proteins)
whose function is to start gene transcription- all set up by
morphogen concentration
Likewise, morphogens
at the anterior and
posterior ends activate
transcription factors
such as “hox” genes
that determine
neuronal identity
what is step 3 of neural development and what happens in it
neurogenesis
why does brain size increase
during development, brains generate lots of neurons
key concept of neurogenesis: stem cell
Stem cell - a cell that can
(1) divide to produce at least one daughter just like itself or
(2) turn into a more differentiated cell (including more stem cells with more restricted potential).
Examples: embryonic stem cell,
neural stem cell, motor
neuronal stem cell etc.
key concept of neurogenesis: progressive restriction of cell fate
So called “European plan”: What you become depends on who your parents are.
So called “American plan”: Who you become depends on your surroundings
“postmitotic”
Neuron can’t divide again
Adult Neurogenesis
Until recently, it was thought that all neurons in the mammalian brain are
“born” (that is, have their last cell division and become irreversibly “postmitotic”) in embryos or right after
birth. So, people thought there were no neural stem cells left in the adult brain.
turns out to be not quite true: Neurogenesis continues at
low levels in a few parts of the adult human brain –especially the hippocampus but not cerebral cortex. Stem cells are in the subgranular zone
(SGZ) surrounding the dentate gyrus and from there they migrate and differentiate into neurons in the dentate gyrus. Thus, some neural stem
cells persist in the adult brain.
Exercise and behavioral enrichment increase their generation or survival, while stress decreases their survival.
Antidepressants may act in part by stimulation their production.
what is step 4 of neural development and what happens in it
Neural progenitors are found in the neural tube near the
central cavity that becomes the ventricles in the brain. This
area is called the sub
ventricular zone.
Radial glia assist in radial migration
Cortex develops in an “inside out” fashion. Different layers are “born” at different periods. Shown by labeling DNA at last
division before neuron becomes postmitotic with radioactive nucleotide (thymidine)
Inhibitory neurons migrate in a different way (laterally
instead of vertically)
Gene mutations (e.g. of the Reelin gene expressed in radial
glia) affect neuronal migration and cause profound disorders
in brain development
Neural progenitors are found in the neural tube near the
central cavity that becomes the ventricles in the brain. This
area is called the…
subventricular zone.
what is step 5 of neural development and what happens in it
differentiation
Lineage and extrinsic factors determine:
Dynamic polarization (axons and dendrites)
Neurotransmitter type
Scientists take advantage of these key programming steps to induce neurons from stem cells (no need to memorize all these signals)
Victor Hamburger
A student of Hans Spemann
(“organizer experiment”). He
left Germany in 1935 due to
rising antisemitism. Took job
at Wash U (St. Louis). There
he developed the chick
embryo as a model organism
to study neural development
A role for the synaptic targets of neurons
When the synaptic target of a
neuronal type (such as a limb bud) is removed early in development before axons enter the limb, few neurons in ventral spinal cord are
present once development is
over…but only on the side of the spinal cord that is ipsilateral (same side) as the removed limb.
what are extra limbs associated with
extra motor neurons on ipsilateral side of spinal cord
Can you formulate a hypothesis that explains
how limb removal or conversely limb addition
would change the number of neurons in the spinal
cord on the ipsilateral side
Victor Hamburger
Rita Levi-Montalcini
In order to decide between these hypotheses they removed the hindlimb (leg of a very young chick embryos) by making a window in the egg and then at various times they counted the number of motor
neurons in the hindlimb part of the spinal cord to see whether the limb ablation inhibited motor neuron proliferation or motor neuron survival. The results were surprising!
First, on the limb-ablated side total number of motor neurons dropped precipitously by more
than 90% arguing that neurons were dying in the absence of limb.
Second on the normal
side neurons were also dying with the same time course as the death associated with limb
ablation. Subsequent studies showed that the contralateral cell death was naturally occurring and had nothing to do with limb ablation.
Third, it wasn’t just motor neurons, the dorsal root ganglion cells also died over the same time.
what is step 6 of neural development and what happens in it
programmed cell death (apoptosis)
In an attempt to better understand how neuronal targets might affect the numbers of neurons that survived, one of Hamburger’s students, Elmer Beuker, discovered that a mouse
sarcoma (tumor) when implanted into the region of the hindlimb of a chick
embryo, stimulated nerve growth into the tumor. Levi-Montalcini noticed enlargement of the dorsal root ganglia (“SP” in figure) and the sympathetic ganglia (“SY”) but not extra motor neurons on the side where the tumor
was situated
they set about to purify
the factor in the tumor that was causing the growth and greater numbers of sensory and sympathetic
neurons
Key to their success at purification was a “bioassay” that LeviMontalcini set up with cultured dorsal root ganglion cells. In the absence of the sarcoma extract the cells just sat there in the dish (upper panel). However with a small amount of sarcoma extract they grew out long processes (bottom panel). With the bioassay Cohen was
able to successively purify the active agent. A breakthrough came when Cohen had gotten the material purified to be either a nucleic acid or a protein and used a snake
venom to destroy the nucleic acid to see if that destroyed the activity seen in the bioassay (it did not- meaning the factor was a protein), but it turned out weirdly, that the venom was thousands of times more
powerful on its own than the sarcoma in causing nerve outgrowth. This led Cohen to look at salivary glands in mammals (as the analog of
the venom producing gland in a snake). Amazingly the male rat submandibular salivary gland was an even more plentiful source of the factor. And with such large quantities it was possible for him to
purify the Nerve Growth Factor (NGF) completely
Nerve Growth Factor (NGF)
NGF is a peptide of consisting of 118 amino acids
It is produced by peripheral end organs innervated by
sympathetic and some sensory (especially pain-sensitive)
neurons. These particular neurons have a special receptor (TrkA) that binds to NGF and initiates a number of
downstream effects including survival and nerve
outgrowth. This “trophic factor” keeps sensory and
sympathetic neurons alive that reach their targets.
The concentration of NGF in the blood plasma is
significantly higher in individuals who have been in a
romantic relationship with another person for less than
12 months [227 pg/ml], than those who are either not in
a romantic relationship [149 pg/ml] or have been in one
for more than 12 months [123 pg/ml]
The trophic factor NGF is part of a gene family
The trophic factor NGF is part of a gene family of Neurotrophins and their trk receptors. Each member of this family has selective effects on a different set of neurons. In the CNS Brain derived neurotrophic factor (BDNF) is most widely expressed and it has many functions including effects on synaptic plasticity.
Gastrulation
the process by which an embryonic blastula (ball of relatively undifferentiated
cells) becomes a layered structure by the invagination and spreading of cells. Forms the
primary germ layers: endoderm (innermost layer, gives rise to the gut, liver and other organs),
mesoderm (middle layer, gives rise to bones, muscles, heart and circulatory system), and
ectoderm (outer layer, gives rise to skin and nervous system)
Neurulation
the process that establishes the neural tube, which eventually develops into the
central nervous system and the neural crest cells, which eventually develop into the peripheral nervous system. Neurulation occurs when the notochord (specialized mesoderm cells) induce
the neural plate from the midline of the dorsal ectoderm. The lateral walls of the neural plate grow and close to form the neural tube. Neural crest cells form from the borders of the neural plate as the tube pinches off and becomes covered with a new layer of ectoderm cells
Regionalization
the establishment of different compartments and patterning of axis within
the developing nervous system
Morphogen
a diffusible signaling protein that can cause cells located at different distances from the source (different concentrations) to adopt different fates. The
morphogen “sonic hedgehog or shh” is released from the notochord near the ventral
edge of the spinal cord and helps pattern the dorsal-ventral axis. Similar programs
using “hox” genes determine neural identity in the rostral/caudal axis
Transcription factor
a DNA binding protein that regulates transcription of target genes. Often, they are key regulators that help activate (or repress) programs that decide which genes are transcribed into RNA and subsequently translated into protein
Neurogenesis
the process by which neurons are produced from stem cells (which can assume any fate) and neural progenitor cells (which have limited potential). As cells divide, their
progeny become more and more fate limited
Adult neurogenesis
until somewhat recently, it was believed that all neurons in the
mammalian brain were “born” very early in development, However, some neurogenesis
continues in a few parts of the adult brain: the dentate gyrus of the hippocampus and
olfactory bulb. These neurons can be integrated into the established adult circuits,
giving hope for therapeutics and replacement of neurons due to injury or degeneration
Migration
neurons are “born” in specific areas containing stem cell and neural precursor populations, and must travel to their final position in the brain. Most of the principle, excitatory
neurons are born near the ventricles (ventricular zone) and migrate radially (usually along radial glia) to form the layers of the cortex. The cortex develops in an “inside out” fashion. Different layers are “born” a different periods, this the deepest layers (5/6) born first and the upper layers
born later and then migrate past the other neurons. Inhibitory neurons are born near the ventral
edge of the ventricles and must migrate horizontally around to their final positions in the cortex
Differentiation
the progressive specialization of developing cells until they establish their final
fate (identity). Both lineage and extrinsic factors determine what type of neurotransmitter is released by the cells, how their axons and dendrites are organized and probably many other properties
Apoptosis
programed cell death. Most types of neurons are generated in approximately 2-
fold excess and about half die later in development, AFTER migration, differentiation and
sending out axons
Neurotrophic hypothesis
the idea that the survival of developing neurons depends
on neurotrophins (a family of secreted signaling proteins) that regulate the survival and
morphology/physiology of target neurons through binding to specific receptors on the
target neurons). The developing neurons have an intrinsic pathway towards cell death unless that pathway is inhibited by trophic factors. Neurotrophins are typically produced by the post synaptic targets
- List and be able to briefly describe the 9 different steps in neural development
- Understand the concept of induction, especially as it applies to the notochord and
regionalization
- Understand the concept of induction, especially as it applies to the notochord and
regionalization
- State the trophic theory and explain how programmed cell death regulates development of the nervous system
- Connect a developmental disorder (or description of one) to dysregulation at a specific stage in early neurodevelopment.
