Overview of CNS development Flashcards

1
Q

What is ‘morphogenesis’?

A

Changes in size and shape during the embryonic development of the nervous system.

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2
Q

What is ‘differentiation’?

A

Process over developmental time whereby an initially homogeneous cell population gives rise to different cell types.

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3
Q

What are the developmental stages of the embryo, from day 0 to birth?

A

> Day 0: Fertilisation and cleavage of the egg
- egg cleaves and forms a blastocyst

> Day 7 (one week): Implantation of blastocyst into uterine wall - formation of embryonic disk
- with 2 layers: epiblast and hypoblast

> Day 14 (two weeks): Gastrulation
- transformation of the 2-layered disk into 3 ‘germ’ layers: ectoderm, mesoderm, endoderm - give rise to all tissues

> Day 21 (3 weeks): Neurulation
- creation of the embryonic nervous system from the ectoderm (neural induction)

> Week 4-5: Tailbud stage
- embryo recognisable with a head and tail

> Week 4-8: Embryonic period

  • organogenesis occurs
  • main tissue and organ systems develop
  • major body features develop

> 3rd month - birth: Foetal period

  • maturation of tissues and organs
  • rapid growth of the body
  • cell proliferation (important for the brain)
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4
Q

What is neural induction?

A

In the process of neurulation (at 3 weeks):
- Ectoderm is induced by the underlying mesoderm to become neural tissue
= morphogenic and genetic changes transform section of the ectoderm into the neural tube
-> ectoderm develops into the nervous system

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5
Q

What happens during early neurulation?

A
At 19-20 days
> Embryo is composed of 3 germ layers
- ectoderm on top
- mesoderm in the middle - includes the notochord
- endoderm

> Neural plate of the ectoderm transforms into neural folds
Somites form in the mesoderm, and give rise to axial muscles
Lateral regions of embryo give rise to the epidermis of the skin
Medial part of embryo give rise to the nervous system

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6
Q

What happens during late neurulation?

A

At 22-23 days
1. Neural folds of the ectoderm approach each other

  1. Somites in the mesoderm have expanded
  2. Neural tube closes and becomes separated
    - one region of neural tube has started to fuse, usually neck region
    - neural tube closes at the anterior and posterior ends
  3. Ectoderm layer has formed over the neural tube
    - > Nervous system becomes subdivided: spinal cord posteriorly and brain vesicles anteriorly
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7
Q

At which stage of the embryonic development does morphogenesis take place?
What happens?

A

At tailbud stage, 4-5 weeks
> Cranial and caudal folding arches the embryo into a “comma” shape
> Lateral folding to enclose all forming internal organs in a covering of the ectoderm -> skin
> Major structures of the developing embryo are already formed:
- branchial arches: elements of lower jaw and neck
- heart
- limb bud (limbs)
- eye
- otic vesicle (inner ear)

-> recognisable appearance

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8
Q

What do we see when comparing embryos of various organisms?

A

They look similar at the tailbud stage (4-5 weeks).

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9
Q

When and how does the formation of the flexures and subdivisions in the neural tube take place?

A

At 5 weeks (embryonic period)
> Folding of the neural tube -> formation of flexures
- at the level of the midbrain
- at the junction of spinal cord and hindbrain
- and at the hindbrain, separating pons from medulla
-> more mature morphology

> In prosencephalon (forebrain)

  • Diencephalon will give rise to nuclei (important collections of neurons): thalamus and hypothalamus
  • Telencephalon will give rise to cerebral hemispheres via an extensive folding process
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10
Q

How does differentiation affect human development?

A

Cells progress from a ‘multipotant’ population, capable of producing a range of cellular derivatives, to cells of specialised identities

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11
Q

What is Waddington’s epigenetic landscape?

A

A metaphor for development and how cells make ‘decisions’ to arrive at their ‘fates’.

  • External influences and interactions between groups of cells instruct the cells on their next developmental step
    e. g. neural induction: neural plate (ectoderm) is influenced by the mesoderm to develop into the nervous system
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12
Q

What are the aspects of neuronal differentiation?

A
  • Morphology
  • Gene expression
  • Neurotransmitter
  • Axon projections and connections

= characteristics of differentiated neural types

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13
Q

What are the developmental steps that lead to differentiation?

A

> Neurogenesis
- cell division occurs to generate neurons

> Cell migration
- young neurons migrate away from ventricular zone

> Axogenesis
- neuron starts to develop processes including axons

> Synaptogenesis
- axons connect with their target neurons and other structures -> synapses

> Cell death or pruning
- regressive events occur leading to the formation of the mature neuron
(brain loses synapses to refine its pathways and balance Glu-GABA ratio)

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14
Q

How does neurogenesis take place?

A

Generation of neurons from radial glial cells, in the neural tube:
> Neural tube has a ventricular zone (with cerebral spinal fluid) and a mantle zone
> In the ventricular zone, radial glial cells undergo cell divisions repeatedly to expand the progenitor cell population
> Some of these divisions give rise to a neuron
> Neuron migrates from ventricular to mantle zone, along the radial glial cell = radial migration
> In mantle zone, further differentiation of the neuron will take place, including extension of the axon

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15
Q

Which neuronal migration generates cortical neurons?

A

> Radial migration (cells migrating along radial glial cells):
- gives rise to excitatory projection neurons: Glutamate neurons, with long axons

> Tangential migration
- gives rise to inhibitory interneurons: GABA neurons, with short axons

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16
Q

Which neuronal migration leads to the formation of the peripheral nervous system?

A

Migration of the neural crest cells to generate peripheral ganglia:
- neural crest cells migrate away from the neural tube to form dorsal root ganglia and sympathetic ganglia

-> formation of peripheral nervous system

17
Q

What are the stages of axonogenesis?

A

As neurons move into the mantle zone and start to differentiate, they develop axons

  1. Post-mitotic neuron
  2. Post-mitotic neuron with symmetrical neurites (processes)
  3. Symmetry breaking produces one axon and several dendrites - one of the neurites becomes an axon
  4. Axon grows longer and dendrites grow out of the cell body
    - their development is in parallel
  5. A neuronal network with synapses forms
    - dendritic spines forming on the dendrites
18
Q

What are the types of synapses?

A

> Axo-dendritic synapses: form on dendrites
Axo-somatic synapses: form on the cell body
Axo-axonic synapses: form on the axon

19
Q

What are the various molecules that play a role in synapse formation?

A

> Transmembrane proteins:

  • Neurexin, expressed by pre-synaptic neuron
  • Neurolegin, expressed by post-synaptic neuron
  • Neuroligin 1 proteins make excitatory synapses
  • Neuroligin 2 proteins make inhibitory synapses

> Cadherins and Syncams: proteins that help consolidate synapse formation

> Scaffolding proteins

20
Q

How does synaptogenesis take place?

A
  1. Neurexin and Neuroligin (transmembrane proteins) bind the pre and post-synaptic parts together
  2. They serve as focus for other proteins to cluster together to form the synapse: cadherins and syncams
  3. Neurexin and Neuroligin recruit specialised groups of proteins into the presynaptic active zones, containing the NT vesicles in the presynaptic terminal
    AND coordinate the assembly of postsynaptic densities, containing the scaffolding proteins and NT receptors
21
Q

What is the process of cell death and pruning?

A

Common phenomenon: approx. 50% of motor neurons die during neural development
> Pruning can occur to axons and dendrites, which disintegrate and the debris is cleared away
> Cell death and pruning:
- eliminate unwanted neurons or connections
- match numbers of pre and post-synaptic cells
- ensure that synaptic transmission and circuit function is optimised
-> synapse pruning decreases the complexity of the synapse landscape

22
Q

How is the autistic spectrum disorder (ASD) associated to synaptogenesis?

A

> Studies in humans have shown that mutation in several genes including Neuroligin4 (Nlgn 4) are linked to ASD

> Nlgn4 is involved in synapse development

  • Gephyrin and GABA A receptor unit are markers of inhibitory synapses
  • these markers are reduced in Nlgn4 knockout mice (mice deficient in Nlgn4 gene) in hypothalamus
  • > Developmental deficit

> Nlgn4 knockout mice show behavioural changes reminiscent of ASD: impairments in social interactions and communication, repetitive behaviours and interests

=> Even though the link between synaptogenesis and behaviour is extremely complex, those studies show that ASD could be modelled using the mouse as our experimental system

23
Q

How is dendritic spine development associated to schizophrenia and ASD?

A

> The number of dendritic spines is reduced in the dorsolateral prefrontal cortex of some schizophrenic subjects
The process of dendrite development and/or pruning is implicated in schizophrenia and ASD

> Mice lacking Fragile X mental retardation protein have more immature, thin spines
Evidence o similar change in humans with Fragile-X

BUT, results from a large variety of studies are conflicting about this