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Neurobiology > Neural Development > Flashcards

Neural Development Flashcards

1
Q

How is a coordinate system set up in the maternal oocyte?

A

All continuous gradients:

Dorsal-ventral: ‘dorsal’ molecule concentrated at ventral side

Anterior-posterior: ‘bicoid’ at anterior; retinoic acid (RA) and FGF at posterior.

Animal-vegetal: specific transcripts (e.g. in Xenopus = Vg1)

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2
Q

What are the stages of developing a combinatorial code in an embryo?

A
  1. Maternal cytoplasmic polarity
  2. Gap genes
  3. Pair-rule genes
  4. Segment polarity genes and homeotic (Hox) genes.

Encouraged by the French flag model

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3
Q

What is the French Flag model? How is it achieved?

A

Where the difference in concentration of a substance is unimportant until a threshold reached.

  • Switches on combinations of TFs
  • Resolution increased by : +ve feedback on itself and -ve feedback on its neighbour.
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4
Q

Outline the stages of nervous system development (rough):

A
  1. Gastrulation allowing mesoderm creation
  2. Invagination to form neural tube
  3. Induction of the floor plate
  4. Separation of mesencephalon (brain) from spinal cord.
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5
Q

What are the molecules involved in setting up a polarised neural tube dorso-ventral?

A

Ventral:
- BMPs
- Activin
- Dorsalin

Dorsal:
Notochord induces floor plate which produces:
- Shh (binds patched receptor)
- Anti-BMPs (noggin; chordin; follistatin) –> These bind BMP molecules stopping them bind their receptor; reducing activation of TGF-β

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6
Q

What are the molecules involved in setting up a polarised neural tube anterior-posterior?

A

At dorsal posterior:
- Wnt highest conc.
- Binds frizzled receptor

At dorsal anterior:
- Sfrp1 highest

At ventral anterior:
- Wnt4 and 7b

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7
Q

What are neural crest cells and what do they form?

A

Collection of multipotent stem cells formed proximal to the neural tube and epidermis (driven by FGF signalling)

Form:
- Neuronal cells (enteric gut neurons; sympathetic ganglia; glial cells; sweat glands)
- Non-neuronal cells (pigment cells; cartilage cells; skeletal elements like teeth)

Shown by ABCD syndrome = albinism, gut neuron disorder, deafness….

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8
Q

What is the experimental evidence for the creation of a dorsal-ventral axis in an embryo?

A
  • Grafting a second dorsal tip on an embryo induces a second neural axis
  • Grafted tip able to recruit new cells
  • BMP at dorsal; sonic hedgehog (shh) at ventral
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9
Q

What evidence led to the discovery of neural inducing genes?

A
  • UV light inhibits development of dorsal structures (including neural)
  • Lithium inhibits development of ventral structures (hyperdorsal)
  • mRNA extracted from hyperdorsal embryo can ‘rescue’ UV treated one

Led to discovery of neural genes: noggin and chordin

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10
Q

What is the general formula for how a signalling molecule induces a response? Use RA as an example.

A
  1. Signal
  2. Receptor
  3. Pathway
  4. TF (genes)

E.g. RA -> RAR -> pathway -> RARE (response element) modulating hox gene transcription.

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11
Q

What evidence suggests that neural tissue is the default? What does activin do?

A
  • Injection of mRNA for non-functional activin receptor
  • Led to induction of neural tissue (that is default)

Activin changes fate of cells to not become neural.
- Follistatin inhibits activin where neural tissue desired.

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12
Q

What evidence suggests the role of the notochord?

A
  • Transplantation of a second ectopic notochord onto neural tube leads to ectopic neurons
  • Removal of notochord leads to hugely reduced neural tissue induction

Notochord induces floor plate which then leads to the induction of neural tissue

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13
Q

What are hox genes? Give evidence.

A

An independent set of TF genes defining a particular region of the body (rhombomere = morphological subdivision).

  • Deletion of Hoxa1 causes loss of rhombere r5 but others unaffected
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14
Q

How is the neural tube specialised to form the hindbrain and spinal cord? (4 points)

A

Activation
- Specialises forebrain

Stabilisation
- Specialises neural and forebrain states

Transformation
- Caudalies tissue forming hindbrain and spinal cord

Sympathetic ganglia arise from the neural crest; parasympathetic from the trunk

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15
Q

Describe the structure of the growth cone:

A
  • Axon terminates in the central domain (houses organelles + microtubules)
  • Transition zone
  • Peripheral domain with filo and lamellipodia
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16
Q

What is the experimental evidence for growth cone movement being independent from the cell body?

A
  • Retinal ganglion cells labelled and time-lapsed movement
  • Growth cone continues to navigate for hours after separation from cell body (contained)
  • Continues to respond to attractive/repulsive cues (local translation of proteins can occur; just not central)
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17
Q

How do growth cones move forward?

A
  • Axons extend their microtubules into the distal tips pushing the GC forward
  • Filopodia extend, exerting a tensile force on the GC
  • Direction: determined by balance of F-actin retrograde flow and myosin based filament retraction (and the proximal recycling of filamentous actin in the transitional zone)
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18
Q

How is the direction of growth cone speed determined?

A

Determined by speed of retrograde flow which is reliant on:
- F-actin assembly rate
- Myosin based filament retraction
- When both in equilibrium no growth

Must be stabilised by microtubule insertion:
- Faster flow increases speed of microtubule shunting out of filopodia
- Thus reduced retrograde encourages stabilisation of microtubules

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19
Q

What is the evidence for microtubules being pushed into the GC forward?

A
  • MT fluorescently labelled
  • An area photobleached with a laser.
  • The spot remains stationary but the tubules move forward, suggesting new MTs are pushed forward rather than synthesised at the tip.
20
Q

What evidence is there for filopodia extending and exerting a tensile force on the growth cone?

A

Evidence for filopodia myosin/actin extension:
- Addition of cytochalasin-β (actin depolymeriser) disrupts the growth (slower) and pathfinding ability of the GC.
- Washing it away allows re-activation of growth cone (suggests continued polymerisation)

Evidence for tensile force:
- Picking up a single filopodia causes the GC to jerk in the opposite direction (due to loss of the tensile force)

21
Q

What is the clutch hypothesis?

A

The link between the actomyosin cytoskeleton (the molecular clutch)
- Altered by the adhesiveness of the surface

Depends on isoform of the integrins expressed:
- Concanavalin-α = very adhesive substrate
- Laminin and fibronectin promote outgrowth
- Changed by context: chick retinal ganglion cells start preferring laminin then switch to fibronectin with decreased α6-subunit expression.

22
Q

What are the principle mechanisms that alter the speed of retrograde flow and allow turning of the growth cone?

A

Asymmetrical flow encourages turning:

  • Assembly of actin at the leading edge
  • Translocation of monomers by myosin motors away from leading edge
  • Enzyme mediated disassembly/recycling in the transition zone
23
Q

What are the intracellular cascades responsible for turning of the GC?

A

Balance between cAMP and cGMP:

Attractive cue:
- Upregulates cAMP
- Amplified by CICR
- Initiates VAMP2 mediated vesicle exocytosis

Repulsive cues:
- Upregulates cGMP
- Low amplitude Ca2+ release
- Calcineurin activated
- Clathrin mediated endocytosis to retract GC

Mutual inhibition between cAMP and cGMP signalling facilitates decisiveness.

24
Q

What are the insect cuticle burning experiments and what do they show?

A
  • Burning a small section allows compensation and regrowth back to CNS
  • Excessive burning – axons end in spiral. Need other axons as scaffold substrate

Shows self organising properties during development and regeneration.

25
Q

Do pioneer axons have a special ability?

A

Ti1 neurons make initial path.
- Important for first time BUT other neurons still manage if pioneers ablated
- Suggests all have innate pathfinding ability
- Suggests others have potential to be pioneers but happy following
- More important for neurons crossing a segmental boundary (to cross or not to cross?)

26
Q

How do neurons navigate?

A

Stepping stones: provide physical landmarks
- Particularly across segmental boundary
- Physical guidance (e.g. radial glia to crawl along)

Guidance cues: provide chemical landmarks (balance of attractive and repulsive cues)
- Secreted molecules (gradients)
- Surface ligands and receptors (e.g. integrins)

Reaction depends on context (which TFs activated – think robo and com)

27
Q

What are the two models explaining the change in reaction to the floor plate after crossing the midline?

A

Changes GC responsiveness after initial exposure to floor plate (attractive than repulsive after signpost)

Shh model: shh induces responsiveness to semaphoring repulsion during midline crossing

Timer switch model: upregulation of 14-3-3 suppresses PKA

28
Q

How is the midline arranged and which genes control the decision of GCs to cross (or not)?

A

Midline provides symmetrical line and is arranged like ladder – provides decision point.

Organised by ventral cells which an secrete repulsive midline signal (Slit)

  • Robo gene discourages crossing
    Commissure gene encourages crossing (temporarily to allow one cross)
  • When mutated no GCs cross
  • Antagonises robo to desensitise GC from Slit.
29
Q

What are neural crest cells?

A

A collection of progenitor cells proximal to the dorsal epidermal layer that give rise to critical areas of the craniofacial and peripheral nervous system.

Induced by dorsalin following neurulation.

30
Q

Which molecules affect GC identity?

A
  • FGF2 induces cholinergic and adrenergic neuron formation
  • Dorsalin (along with other dorso-ventral cues) induces neural crest formation
31
Q

Give examples of molecular markers which neurons use to navigate:

A

Floor vs. roof plate:
- shh provides initial attractive gradient towards floor plate
- BMPs repulse from roof plate
- Neutrin provides ‘carpet’ for axons to grow along (attractive and facilitates movement)

Cerebellum:
- Neurons crawl along particular radial glia (fan out from ventricles)
- Use αv integrin on glia cells to bind

32
Q

How does the birth position (and time) of a motor neuron affect its final pathway and destination?

A
  1. Decide which neurons will be motor neurons (by [shh]) = early born neurons (in LMC)
  2. These early born neurons produce RA
  3. RA gradient signals to late born motor neurons to change their gene expression dependent medial-lateral position – mLMCs are early born; lLMCs are late born
  4. Means mLMCs express Islet1 factor and retinaldehyde dehydrogenase-2 (RALDH2) while lLMCs express TF Lim1
  5. This changes the behaviour of neuron groups which progressively gets more disparate
33
Q

How is spatial visual information retained in the retinotopic map?

A
  • Retinal ganglion cells project to specific regions in tectum
  • Relative spatial relationships and axonal terminations conserved
  • Determined by original anatomic location (BF-2 on temporal side; BF-1 on nasal side)
  • BF changes reaction to engrailed in tectum (highest concentration in posterior which is attractive to BF-1)
34
Q

How is the behaviour of a developing motor neuron changed to map motor system?

A
  • Achieved by adhesion matching of GC to surface (using cell adhesion molecules (CAMs)) and guidance cues (e.g. netrins/semaphorins).
  • Leads to attractive and repulsive cues
  • E.g. Expression of guidance receptor Eph-B1 (ventral) or Eph-A4 (dorsal) causes choice between dorsal or ventral limb
35
Q

How do BF1 and BF-2 help to map the visual system spatially?

A

Due to expression of genes: BF-2 on temporal side; BF-1 on nasal side
- Changes reaction to Engrailed expression in tectum (highest in posterior so attractive to BF-1 expressing neurons)
- Engrailed-2 repels temporal axons and attracts nasal axons
- Taken up by nasal axons as TF
- Temporal neurons go to anterior (repulsion from posterior area by ephin expression)
- Nasal to posterior

36
Q

What do the striped carpet assays show?

A

Alternate stripes of posterior and anterior tectum:
- Posterior has high engrailed-2 concentration
- Posterior induces ephin expression

Shows temporal axons are very anterior preferring while nasal have little preference.
- Temporal repelled by ephin expression

37
Q

Which experiments suggest that retinal axons retain their original identity?

A

Sperry’s chemo affinity Map: turning eye upside-down leads to upside-down view of world (neurons do not re-navigate)

Replacing dorsal half of retina with a ventral from a donor results in all axons going to same place (act the same)

38
Q

What is the timeline of the NMJ formation?

A
  1. Post-synaptic pre-pattern: AChR receptors begin to aggregate at presumptive synaptic regions
  2. Growth cones arrive at site
  3. AChRs aggregate at innervation site
  4. Agrin deposited (MuSK) activated; triggering intramuscular cascade
  5. ACh released from nerve terminal diffuses across
  6. Binding of ACh to AChRs causes Ca2+ influx
  7. Synaptic refinement occurs: extra-synaptic AChRs disperse through internalisation
39
Q

What changes occur after growth cone arrives at the NMJ?

A
  • Extra filopodia retract (localisation)
  • Growth cone changes to bouton-like shape
  • AChR clusters aggregate and move due to wnt signals from pre-synaptic side
40
Q

How does Agrin help to make precise synapses?

A

Ensures both sides are functionally and spatially in register:
- Deposited by postsynaptic side to protect desired AChRs during synaptic refinement
- Activates MuSK which degrades calpain (preventing AChRs from being degraded by calpain)

41
Q

What is the organisation of the agrin receptor complex?
Which molecules are involved?

A
  • Lpr-4: part of the Agrin receptor complex which binds MuSK – assists in pre-synaptic differentiation
  • MuSK: muscle specific receptor tyrosine kinase triggers AChR clustering
  • Rapsyn: scaffolding protein
42
Q

What is the experimental evidence for AChR clustering prior to GC arrival?

A
  • AChR labelled with ▫ α-bungarotoxin (binds strongly)
  • Under functional microscopy their existence is seen before meeting
43
Q

How was agrin identified?

A
  • Used the electric organ of a torpedo ray (a giant cholinergic synapse) as source of basal lamina to purify
  • Agrin identified as necessary for synaptogenesis (maintenance)
  • Agrin knockout in mice leads to impaired NMJ formation
44
Q

What evidence is there that agrin is anti-dispersal rather than synapse inducing?

A
  • AChR clusters form without Agrin (e.g. in genetic mutants)
  • Live imaging of NMJ formation shows AChR clustering before and in the absence of motor neuron innervation
  • Removal of dispersal agent and Agrin (in mutants) results in synapse formation (no dispersal signal; no anti-dispersal needed)
45
Q

What are the different ways that synapses are aligned in the CNS?

A
  • Bidirectional organisation (e.g. neurexin pre-synaptic and neuroligin post-synaptic link to mutually co-activate each other)
  • Anterograde organisers (post-synaptic receptor with pre-synaptic signalling molecules secreted)
  • Retrograde organisers (pre-synaptic receptor with post-synaptic signalling molecules e.g. FGF7 binds to FGFR)
  • Glial derived organisation (e.g. astrocyte secretes neuroligin1)
46
Q

How do different scaffolding and trans-synaptic formation molecules during synapse formation dictate the type of synapse?

A

Scaffolding:
- Gephyrin in glycine terminals
- Stargazin for glutamate terminals
- Rapsyn for NMJs

Signalling molecules:
- E.g. a retrograde organised synapse with an FGFR on the pre-synaptic side will become inhibitory if FGF7 binds or excitatory if FGF22 binds.

Neurobiology (7 decks)

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