Transcript June 20_Neurodevelopment

Neurodevelopment
Mon, June 20th
How Does the Nervous System
Develop?
Neural crest specification: migrating into genomics. Laura S. Gammill & Marianne Bronner-Fraser
Nature Reviews Neuroscience 4, 795-805 (October 2003)
Nervous System Beginnings
• Embryos are initially made of a single sheet
of cells.
• This cell layer undergoes gastrulation, an
inward folding that produces 3 cell layers:
– Ectoderm (outside)
– Mesoderm (middle)
– Endoderm (inside)
The Notocord
• Gastrulation forms the notocord (a
tube of mesoderm cells).
• Above the notocord lies the
ectoderm that gives rise to the
nervous system (neuroectoderm)
• The notochord also sends signals
to make certain neuroectodermal
cells become neural precursor cells,
a process called neurulation.
Neurulation
• BMP, Wnt, retinoic acid, Sonic
Hedgehog, and FGF are all important
signaling molecules for neurulation.
• The neuroectoderm cells exposed to
these signals thicken into the neural
plate on approx. day 16 of development.
Nervous System Formation
• The neural plate folds inward to create
the neural tube on approx. day 21. This
is the basis for the brain & spinal cord.
• Some of the neural precursors will
create neuroblasts; these are the basis
for neurons.
Neural
Tube
Neural Crest
• The cells at the dorsal (“top”) part of the
neural tube are called the neural crest cells.
• These cells form the basis for sensory relay
neurons to the thalamus.
• At the ventral (“bottom”) portion is the
floorplate. These cells form primary motor
neurons sent to the muscles.
But How Do These Cells Know
What to Become?
• BMP and Wnt
chemical signals are
expressed at high
levels at the dorsal
neural crest cells.
• Sonic Hedgehog (Shh)
is expressed in high
levels at the ventral
region (floorplate).
• These chemicals form
a concentration
gradient from high to
low.
From Lecture by Pete Wenner, Emory
University , 2007
Dorsoventral Patterning
• The amount of the
chemicals that a
cell is exposed to
influences how it
develops.
• The effects of this
concentration
gradient on
development is
called dorsoventral
patterning.
From Lecture by Pete Wenner, Emory
University , 2007
Summary
•
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Gastrulation creates an inward folding of cells to create three
layers, and forms the notocord.
Above the notocord, neuroectoderm cells give rise to the
nervous system.
In neurulation, chemical signals from the notochord make
certain neuroectodermal cells become neural precursor cells.
These neural precursor cells thicken into the neural plate.
The neural plate folds inward to create the neural tube (brain &
spinal cord).
Neuroblasts will continue to become neurons.
The dorsal end of the neural tube contains neural crest cells.
The ventral end of the neural tube contains the floorplate.
High levels of BMP and Wnt signals at the neural crest influence
the development of sensory cells.
High levels of Sonic hedgehog signals at the floorplate
influence the development of motor neurons.
This concentration gradient of BMP, Wnt, and Shh and its
effects on development is called dorsoventral patterning.
The Formation of Brain
Subdivisions
http://faculty.washington.edu/chudler/dev.html
How Does the Brain Form?
• The rostral (“front”)
part of the neural
tube undergoes
several folds and
changes to shape it
into:
– Prosencephalon
(Forebrain)
– Mesencephalon
(Midbrain)
– Rhombencephalon
(Hindbrain)
Neuroscience. 2nd edition.
Purves D, Augustine GJ, Fitzpatrick D, et al., editors.
Sunderland (MA): Sinauer Associates; 2001.
Prosencephalon
• Telencephalon
– Cerebral Cortex
– Hippocampus
– Basal Ganglia
• Diencephalon
– Thalamus
– Hypothalamus
– Optic Cups
Mesencephalon
• Superior Colliculus
• Inferior Colliculus
• Midbrain Tegmentum
Mesencephalon
Future cerebral
aqueduct
Rhombencephalon
• Metencephalon
– Cerebellum
– Pons
• Myencelencephalon
– Medulla
And How Do These Regions
Know What to Become?
• Once again, a
concentration
gradient.
• This time, it’s a
gradient of FGF and
Retinoic acid, which
affect the
expression of
homeobox (Hox)
transcription
factors.
• This is known as
rostrocaudal
patterning.
http://faculty.pnc.edu/pwilkin/homeobox.html
What If Things Go Wrong?
• Changing the expression of even
just one homeobox transcription
factor can have a huge effect!
Matsuo et al, 1995
Summary
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The rostral neural tube forms the basis for the brain’s
subdivisions.
Prosencephalon (Forebrain)
– Telencephalon
• Cerebral Cortex, Hippocampus, & Basal Ganglia
– Diencephalon
• Thalamus & Hypothalamus, Optic Cups
•
Mesencephalon (Midbrain)
– Superior & Inferior Colliculi, Midbrain Tegmentum
•
Rhombencephalon (Hindbrain)
– Metencephalon
•
Cerebellum & Pons
– Myelencephalon
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•
Medulla
A concentration gradient of FGF and Retinoic acid help direct
the development of these subdivisions.
This gradient affect the expression of homeobox (Hox)
transcription factors, and the process is known as rostrocaudal
patterning.
Changes in even one Hox transcription factor can have
devastating results.
Developmental Disorders
http://embryology.med.unsw.edu.au/
Anencephaly
• Absence of a large portion of the
scalp, skull, and brain, particularly
the frontal cortex
• Often do not
survive birth
• Are blind, deaf,
unconscious,
and unable to
feel pain
Holoprosencephaly
• Severe skull and
facial deformities
that often result in
death before birth
• Severity depends
on degree of
malformation
• May also
experience
seizures &
language, vision,
or hearing
problems
Griffiths, Paul D., Variend, Dick, Evans, Margaret, Jones,
Angharad, Wilkinson, Iain D., Paley, Martyn N. J., Whitby,
Elspeth. Postmortem MR Imaging of the Fetal and Stillborn
Central Nervous System. AJNR Am J Neuroradiol 2003 24: 2227
Hydrocephalus
• Symptoms:
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Increased head size & downward gaze
Seizures
Separation of bones of the skull
Abnormal Reflexes
http://www.seattlechildrens.org/medical-conditions/chromosomal-genetic-conditions/hydrocephalus/
Spina Bifida
• Associated with orthopedic
deformities, and sometimes belowaverage intelligence, depression,
and gastrointestinal difficulties
• “Split spine”
Rett Syndrome
• Characterized by deficits in
“learning, speech, sensory
sensations, mood, movement,
breathing, cardiac function, and
even chewing, swallowing, and
digestion”
• May also include seizures
• More common in females
From RettSyndrome.org
Tourette’s & Tic Disorders
• Repeated vocal & motor tics
(involuntary movements or
vocalizations)
• More common in males
• Extremely high co-morbidity with
other developmental
disorders
• Likely inherited
From tsa-usa.org
Autism Spectrum Disorder
• Significant Impairments in social
interactions and verbal & non-verbal
communication
– Restricted patterns of behavior, interest, and
activities
• Repetitive behaviors & insistence on
routine
• May also exhibit sensory problems or
sensitivity
• Symptoms usually develop before 3
years of age
Asperger’s Syndrome
• Specific type of Autism
Spectrum Disorder
– Show significant social
impairments
– Restricted and repetitive
stereotyped behaviors
– May be clumsy
– Often quite verbal &
usually very intelligent
http://static.open.salon.com/files/dustin_hoffman_rain_man121823
6383.jpg
• Affects about 1 to 36
persons per 10,000
people
Fetal Alcohol Syndrome
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Intellectual and learning disabilities
Attention deficits & hyperactivity
Delayed language
Coordination
deficits
• Sensory
problems
Wattendorf, D. J. and M. Muenke (2005). "Fetal
alcohol spectrum disorders." American family
physician 72(2): 279-282, 285.
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