Neural development

What are the 6 steps outlined in neural development?

• neural induction - neural plate

• patterning in neural plate and tube

• cell generation, death and migration

• cell differentiation, connections

• area specialisation

• early neural activity, plasticity

How does formation of the neural plate take place?

• notochord appears in the mesoderm

• notochord secretes growth factors (SHP + BMP) which stimulate differentiation of the overlying ectoderm into neuroectoderm

• forms neural plate

• groove in plate has folds which fuse to form neural tube

What is the neuroectoderm?

a specialized layer of embryonic ectoderm cells that forms the neural plate during early gestation, serving as the precursor to the entire central nervous system

What does the neural tibe compartmentalise into?

forebrain, midbrain, hindbrain and spinal cord

What can problems with closing cause?

• spinal bifida

• anencephaly

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When closing, what forms?

• stem cells escape

• form the neural crest

• important for all cells as they migrate from crest for glia etc

What are the two ways the neural tube is patterned?

• ventro-dorsal

• rostro-caudal

What does the sonic hedgehog protein induce the formation of?

floorplate

What does the floorplate then induce?

ventral motor neurons

Where is bone morphogenetic protein 4 expression and what does it induce?

• roofplate

• the formation of commissural interneurons

What are BMPs more improtant for then?

dorsal area

Bone morphogenetic proteins:

• Specify the roof plate and subsequent dorsal horn formation

• Comes from overlaying ectoderm

Sonic hedgehog proteins:

• Specify floor plate and ventral motor neurons

• From notochord

What gene determines rostro-caudal patterning?

• Hox genes

• expressed in a strict order and hold the patterning

• mutation in genes lead to particular area affected

What is a rhombomere?

• regional differences in the rostro-caudal axis

• hindbrain segments contain cranial nerve nuclei

What is a homeotic gene?

gene which, when mutated, causes convesion of one part of the body into another

What are progenitor cells?

early descendant of a stem cell

Where do progenitor cells ‘start’?

ventricular zone

What are different types of progenitor cells?

• neuroepithelial cells

• radial glial cells

• short and intermediate (found in humans)

What a radial glial cells?

the neural progenitors that give rise to all the neurons and astrocytes of the cerebral cortex

What are the two types of mitosis progenitors do?

• direct (assymetrical)

  • from radial cells to neurons

  • one stays in ventricular zone for more divisions

• indirect (symmetrical)

  • radial to intermediate progenitors to neurons

Steps of direct neurogenesis?

• An RGC divides.

• One daughter remains an RGC (self-renewal).

• The other daughter differentiates directly into a neuron.

Features of direct and when does it dominate?

• Fast and relatively simple.

• Produces fewer neurons overall because each neurogenic division yields only one neuron.

• Predominates during early cortical development.

Steps of indirect neurogenesis?

• An RGC divides to produce an intermediate progenitor cell

• The IPC migrates into the subventricular zone (SVZ).

• The IPC divides one or more times.

• These divisions generate multiple neurons.

Features of indirect and when dominates?

• Amplifies neuronal output.

• Produces more neurons from a single progenitor lineage.

• Important for cortical expansion in mammals.

• Particularly prominent in primates, where additional progenitor types (e.g., outer radial glia) further increase neuron production.

What is ASPM?

• Abnormal Spindle-like Microcephaly-associated gene

• critical regulator of embryonic brain development.

• Primarily known for controlling mitotic spindle function, it dictates the orientation of cell division and ensures that neural stem cells proliferate symmetrically to build a massive pool of neurons before differentiating

What is the Zika virus?

• mosquito born illness

• infection during birth can cause severe microcephaly

  • head smaller than normal because brain not developed properly

What happens with the amount of neurons in early life?

• decreases due to cell death

• transient dynamic scaffolding

• 80% die before 1st bday- only need them to help form rest

How do most glutamergic cells migrate?

• radially/(medially)

• from ventricular zone upwards to cortical layer

How do most GABAergic cells migrate?

• tangentially

• go to sides perpendicular

How do radial glial cells migrate?

• The cells migrate by moving along thin fibres emitted by radial glial cells towards the pia and the order at which they arrive at the cortex aligns with their destiny for which layer they’ll make up.

Who demonstrated the role of radial glial cells by using a vector with green fluorescent protein to find that radial glial cells act not only as neural progenitors but also as scaffolding for these migrating neurons produced?

Noctor et al (2001)

What has an important role in determining fate of neurons?

transcription factors

Example of a intracellular protein signal that can help to form the stereotypical architexture of cortical axons and dendrites?

• semaphorin A

• protein secreted by cells which repels growing pyramidal axons causing them to stream away from the pial surface while attracting growing dendrites leading them towards the brain surface

Example of defect caused by disrupted migration?

• lissencephaly - smooth brain

• leading edge artifacts

  • axons don’t go far enough

  • layers not ordered as they should be

Possible causes for lissencephy I think:

• order effect, neurons not in layer they’re supposed to be

• correlation between progenitors and folding

• overshooting of neurons

What can affect migration using chemical gradients?

molecular guidance

Example of molecular guidance and how it works?

• necterin

• cue that guides axon direction

• generated in floorplate of spinal cord

• interneurons send growth cones to floorplate

• motor neurons find necterin repulsive so exit dorsally

  • only neurons which exit SC dorsally

Once connection with the superior colliculus is established what happens with the connection with the spinal cord?

• eliminated

• motor cortex will need spinal cord though so wouldn’t eliminate

• selective axon elimination

Common drug that causes damage in development?

foetal alcohol syndrome

What is a growth cone?

the tip of an advancing axon

What do molecular guidance cues do?

• growth cones can be attracted or repelled

• molecular cues can be local (substrate bound) or long range (diffusable)

• a given molecule can be both attractive and repulsive

Why do we need to refine connections?

• initial connections can be imprecise

• incorrect target nucleus

• incorrect location within target

How can we regulate the connections?

• neuronal death

• axonal retraction

• synapse elimination

What provides a substrate for neural plasticity?

strategies aka more axons connecting to targets during development so they are then pruned through retraction or degeneration

What are master genes?

• in ventricular and subventricular shape brain

• determine when transcription factors expressed in germinal zone

• investigate using fake brain

Slides on axon elimination?

What is Hebb’s hypothesis?

• cells that fire together wire together

• LTP, NMDA receptors, LTD

• connections strengthened if used together

What is an important debate influencing development?

• nature nurture

• development is a critical period to shape

What did Jenkins et al (1990) do?

What did Hamasaki et al (2004) do?

• manipulating levels of transcription factors in mice, you can see structural alterations in whole areas within the brain, showing manipulated development of the brain leading to altered structure

• mice genetically engineered to produce less EMX2 showed expansion of anterior cortical areas eg motor and shrinkage of posterior areas eg visual, with knocked out PAX6 showing the opposite response in a double dissociation

What does cell death reflect?

• competition for trophic factors and ensures efficiency

• pruning of axons through retraction or degeneration can help to develop the precise connectivity found in the adult brain.

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