Download Development of CNS

CNS Developmental
Anke van Eekelen, PhD
Telethon Institute for Child Health Research
(Some slides are modified versions of
Prof. Alan Harvey’s Neuroscience lecture at ANHB
and Dr. Joanne Britto’s Dev Neuroscience lecture from 2003)
Central Nervous System
Lateral view of the ventricles of the brain
Dorsal view of the spinal cord
•
The brain is an astonishingly complex
structure.
•
However not only is it an amazing
structure it is also, to a large degree, self
assembling.
•
When development goes wrong it causes
great problems as, unlike for example
cardiac problems, it does not always lead
to death
•
About 1.3% of total births have some
neural abnormality
Comparative neurology
optic lobe
olfactory bulb
cerebral cortex
cerebellum
forebrain
CODFISH
pituitary
olfactory bulb
cerebellum
HORSE
optic lobe
forebrain
cerebellum
olfactory bulb
cerebral hemisphere
FROG
optic lobe
forebrain
superior and inferior
colliculi
olfactory bulb
cerebellum
HUMAN
cerebellum
ALLIGATOR
olfactory bulb
The degree of complexity of the brain in the different
vertebrate species reflects its evolution.
forebrain
cerebellum
olfactory bulb
GOOSE
optic lobe
The basic subdivisions of the forebrain, midbrain and
hindbrain are seen in all vertebrates and during
evolution the most striking changes have taken place in
the rostral part of the forebrain, which gives rise to the
olfactory bulb and the telencephalon.
Development of the CNS
Formation of major brain divisions
via
Flexures and swellings of neural tube
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•
Prosencephalon
Forebrain – cerebral hemispheres (cerebral cortex, basal ganglia,
lateral ventricles etc) - Telencephalon
•
•
Diencephalon
Thalamus, hypothalamus, epithalamus
•
•
Mesencephalon - (cephalic flexure)
Midbrain
•
•
•
Rhombencephalon – (pontine and cervical flexures)
Metencephalon – pons, cerebellum
Myelencephalon - medulla
•
Spinal cord
More specifically:
1- Specification of
neural tissue
2- Origin, birth and
migration of cells
3- Acquisition of cell
phenotype
4- Formation of
correct connections
1- Specification of neural tissue
&
neural tube formation
Gastrulation stage
Neural default model of induction
Frog blastula
Ectoderm
(animal cap)
Ventral
Meso
Meso
Endoderm
(vegetal region)
Mesoderm
(marginal zone)
Dorsal
Marginal zone
Endoderm
Organizer
(Nieuwkoop centre)
BMPs (↑ectod diff/↓neuroectod diff)
BMP antagonists
(chordin, follistatin, noggin)
Weinstein and Hemmati-Brivanlou Curr. Opin. Neurobiol (1997) 7:7-12
Formation of neural plate, neural groove and neural tube
22-23
days
Human neural tube closure
Anterior neuropore
22 days
23 days
Normal
Anencephaly
Spina bifida
Dorsal and transverse sections
Anterior and Posterior neuropores
are open to amniotic fluid.
Neural tube closure in mammals us initiated at several places along the
anterior-posterior axis.
Different neural tube defects are caused when various parts of the neural tube
fail to close.
Failure to close the human posterior neural tube at day 27 results in spina bifida.
Failure to close the anterior neural tube results in a lethal condition, anencephaly. In this condition, the
forebrain remains in contact with the amniotic fluid and subsequently degenerates.
Anterior neuropore
23 days
ns
pores
Normal
Anencephaly
Spina bifida
Neural crest cells and peripheral NS
2- Origin, birth and migration of CNS-cells
Neuroepithelial cells “bounce” up and down
Cell migration and radial glia
3- Acquisition of cell phenotype in CNS
Signalling centres
Isthmus - midbrain/hindbrain boundary
mouse
Shh
Wnt1
Fgf8
Dopaminergic neurons
Serotonergic neurons
Wurst and Bally-Cuif Nature Rev Neurosci 2001 2:99-108
chick
What is a morphogen?
Diffusible factor that carries information relating to the position in the embryo, and thus
determines the fate of cells perceiving this information
Secreted factors Shh - Sonic hedgehog, Fgf8 - Fibroblast growth factor 8
vs
Transcription factors Wnt1, En - Engrailed, Pax 2/5/8
Neuronal differentiation
Specification of neuronal identity by SHH
Neuronal
induction
SHH expression
V1, V2, V3 interneruons; MN motor neurons; FP floor plate; N notochord
• SHH is a morphogen
• SHH can induce naive neuroepithelial cells to differentiate
• SHH is secreted from the notochord and decreases in concentration towards the
dorsal neural tube
• Concentration specific induction of floor plate, motorneurons and interneurons
Briscoe and Ericson Sem Cell Dev Biol (1999) 10:353
Patterning
Hindbrain segmentation
(AP Axis)
Identity is conferred onto each
rhombomere by the expression of
different transcription factors
Hox gene family of proteins
Sek gene family of proteins
Rhombomere 1 (metencephalon) is
not specified by these transcription
factors...
Lateral view of a 48 h chick embryo
Lumsden and Krumlauf Science 1996:1109-1115
Patterning
Hindbrain segmentation
(AP Axis)
Why form segments?
Hox genes encode positional value along the
AP axis
This forms developmental compartments
that provide a way of allocating blocks of cells
with distinct properties
Restriction of neuron axonal projectories
(cranial nerves V, VII, VIII, IX)
Confer rhombomere-specific identities to
motor neurons
Flatmount of neural tube
Lumsden and Krumlauf Science 1996:1109-1115
4- Formation of correct connections
Rodent brain
Human CNS
Synaptogenesis and Synaptic Pruning
Adolescent brain maturation
Human Brain Development; Thompson & Nelson 2001