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DEVELOPMENTAL NEUROBIOLOGY > DEVELOPMENTAL NEUROBIOLOGY > Flashcards

DEVELOPMENTAL NEUROBIOLOGY Flashcards

1
Q

Compare nervous system evolution in vertebrates and invertebrates

A

In both, neurogenic region in next to ectoderm (future skin) and neurogenic region migrates
In vertebrates, neurogenic region is next to mesoderm that involutes dorsally and the neural cells form neural plate
In invertebrates, individual neuroblasts delaminate, migrate inwards ventrally and then coalesce to form the ventral nerve cord

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2
Q

Neurogenic fate occurs when…

A

High levels of Nodal give organizer
Organizer expresses Gsc which upregulates BMP antagonists that are secrete and act on neural plate
BMP/dpp signalling is INHIBITED by chordin/sog/noggin/follistatin

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3
Q

Sox2 is a TF required for…

A

Stem cell maintenance/ growth of neural plate

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4
Q

BMP signalling pathway occurs by…

A

Receptor phosphorylated
Leads to phosphorylation of downstream effectors
SMAD-158 phosphorylated, causing a conformational change, allowing it to enter nucleus and act as a transcription factor

  • In Shh signalling, transcription factor is Gli3
  • In Wnt signalling, transcription factor is beta-catenin
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5
Q

What causes neural plate to roll into neural tube?

A

A band of F-actin in apical domain constricts

  • Molecules can interact with F-actin to cause constriction
  • Lack of folate leads to failure of tube to close
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6
Q

As neural plate is induced, dorsal mesoderm undergoes CONVERGENT EVOLUTION and self differentiates into

A

AE=anterior endoderm
PM=prechordal mesoderm
N=notochord

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7
Q

Explain the difference between HEAD AND TRUNK MODEL and the ACTIVATION-TRANSFORMATION MODEL

A

Head and trunk = AE/PM induce brain like TFs
N induce spinal cord like TFs

Activation-transformation=all of neural plate under influence of AE/PM’s anteriorising TFs
As notochord forms, it releases posteriorizing TFs that promote posterior fate in adjacent neural plate cells

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8
Q

What TFs induce anterior and posterior fate?

A

Retinoic acid and Wnt promote posterior fate
RA and Wnt antagonists promote anterior fate

Retinoic acid induces different pattern of Hox transcription

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9
Q

Knockout of Hoxa1 and Hoxb1 shows their requirement in…

A

Rhombomeres 4 and 5 and abducens nerve

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10
Q

Midbrain cells form at boundary between…

A

RA and Wnt antagonist expression from anterior forebrain cells
And
RA and Wnt expression from posterior hindbrain cells

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11
Q

How does neural crest and PNS form?

A

Neural plate border begins to express Msx1
Acts with Wnt to upregulate TFs that characterise ‘neural crest cells’
- c-myc/Sox9 are genes that promote proliferation, multipotency and inhibit cell death
Neural crest cells upregulate TFs that promote epithelial-mesenchymal transition
Allows neural crest cells to delaminate

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12
Q

What does PissOffin do?

A

PissOffin in posterior somite repels neural crest cells

Enhances the repellent effect on Sema3a on DRG axons

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13
Q

What are roof plate cells?

A

Neural crest cells stay to form roof plate cells
RPC form neural tube

*BMPs/Wnts expressed by roof plate cells induced different sets of progenitor cells that will differentiate to distinct neuronal subsets in dorsal spinal cord

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14
Q

Notochord secretes ………. which induces ventralisation

A

Shh

*Progenitor domains made up of proliferating bands of cells established through opposing action of BMPs/Wnts (dorsally) and Shh (ventrally

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15
Q

Knockout of Shh leads to ….

A

Holoprosencephaly, lack of pituitary gland, abnormal limb digits and lack of ventralisation

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16
Q

Along A-P gradient of brain, Shh induces ….

A

Hypothalamic neurons in the forebrain
Dopaminergic neurons in the midbrain
Serotonergic neurons in the hindbrain

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17
Q

Explain the two divisions of radial glia cells

A

Symmetric division to produce two radial glia cells
Asymmetric division to produce a neuron and a radial glia cell
Neuron uses scaffold provided by radial glia cell sister to radial migrate away from the ventricular zone (VZ)

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18
Q

Explain interkinetic migration

A

Radial glial cells undergo interkinetic migration
During G1 and S, nucleus moves laterally
During G2 and M, nucleus returns medially
Lateral attachment breaks in cytokinesis

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19
Q

Asymmetric or symmetric division depends on….

A
  1. Asymmetric or symmetric division of intracellular determinants
  2. Delta-Notch signalling
    If more Delta, (or Acheate scute) expressed then neural fate
    If more Notch expressed then radial glia fate
    Inhibitory signal sent between ligand (Delta) and receptor (Notch)
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20
Q

Explain formation of the preplate in the cortex

A

Cajal Retzius cells set up the marginal zone - die in postnatal period
Subplate cells set up the intermediate zone
Later migrating neurons migrate inbetween these two zones to form the cortical plate

*Early born precursors radially migrate to deep layers
Fate of early born precursors is plastic
*Later born precursors radially migrate to superficial layers
Fate or later born precursors is fixed

*Loss of Reelin mutations lead to failure of Cajal Retzius cells and subplate cells to separate (affecting migration), disrupting cortex. This leads to lissencephaly in humans

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21
Q

Radial glia cells give rise to adult stem cells

Two major zones formed from radial glia are:

A
  • Subventricular zone of 4th ventricle –> olfactory neurons migrate via the Rostral Migratory Stream of the olfactory bulb
  • Denate gyrus of hippocampus –> granule neurons
22
Q

Give examples of tangential migrations in the cortex and cerebellum

A

In the cortex, inhibitory interneurons of the cortex tangentially migrate in from the subpallium
In the cerebellum,
- Anterior rhombic lip daughters migrate tangentially to form the External Germinal Layer. They then migrate radially to Inner Granular Layer to form granule neurons
- Posterior rhombic lip daughters migrate tangentially to ventral hindbrain to form pontine nuclei and inferior olive

23
Q

What factors control cerebellar development?

A
  • ATOH1 knockout leads to no foliation, no inner granular layer and no pontine nuclei
  • Sonic HH released from Purkinje cells, stimulates mitosis in External Germinal Layer
  • Loss of Reelin or reelin receptor leads to disruption of Purkinje cell layer

*Reelin expressed by granule neurons above and below Purkinje cell layer

24
Q

What are the two theories for how connectivity is achieved?

A

-WEISS RESONANCE THEORY
Random neuronal outgrowth occurs to all targets followed by elimination of non-functional connection
- SPERRY CHEMOAFFINITY HYPOTHESIS
Direct and specific outgrowth with axons following cues

*Sperry’s experiment: cut optic nerve and nasal axons grew back to the right place. Motor axons also grew to the correct place when cut or reversed in chick embryo

25
Q

Give examples of:

  • Early axons (pioneers) forming an axon scaffold on which later axons (followers) can extend
  • Growth cones appearing to react at specific points in pathways - ‘stepping stones’ or ‘guidepost’ cells
A
  • Subplate neurons extend from cortex to thalamus producing a scaffold for LGN neurons to extend to cortex
  • Ti1 growth cone in the grasshopper limb bud makes a specific turn when it reaches the limb body boundary and turns again towards Cx1
    Ablation of Cx1 causes Ti1 growth cone to stall at the other side of the limb body boundary
26
Q

How does a neuron ‘know’ which end the growth cone should be?

A

Axons have highly polarised microtubules, +end towards growth cone indicates where axons are forming

Different microtubule organisation in each structure is due to the localisation of different types of microtubule associated proteins (MAPs)
- axons express Tau, whereas dendrites have Map2

27
Q

What underlines axon choice for growth cone?

A

Microtubule (MT) stabilisation is critical for axon initiation

Stabilised microtubules (acetylated) are present in the newly polarised axon 
Artificial stabilisation of MTs by localised taxol application to one neurite selects for axon formation 
Competition between axons stabilise MTs and some kind of feedback loop to prevent neurites being selected
28
Q

Describe the anatomy of a growth cone

A

Three domains - central, transitional and peripheral
Lamella and filopodia are made up of different kinds of F-actin
In lamella, the actin bundles are crosslinked into a net
In filopodia, the actin bundles are polarised to form large bundles
*F-actin “treadmills” in a resting growth cone

29
Q

Reorganisation of the growth cone occurs when a growth cue is met: What occurs to cause the reorganisation?

A
  • Molecular Clutch is engaged and backward actin treadmilling stops - results in forward movement of filopodia
  • F-actin accumulates to stabilise filopodia
30
Q

Non-permissive guidance cues include:

A

-Semaphorins
Either membrane bound or secreted (Sema3a)
*In mice lacking Sema3a, axons stray into wrong territories
Blocking Sema1 and Sema2 function disrupts/stalls Ti1 guidance

-Ephs (receptors) and ephrins cause repulsion between cells
They have a reciprocal/mutually exclusive pattern of expression
*Compartmentalise embryo into discrete domains e.g. rhombomeres

  • Commissural axons repelled by roof plate BMPs (BMP7)
31
Q

Permissive guidance cues include:

A
  • Laminin is a growth promoting extracellular matrix protein localised in the optic nerve
    Does not dictate direction of axon growth, only that axon can grow there
  • Commissural axons attracted to floor plate by chemoattractant Netrin and Shh
32
Q

What determines whether an axon can cross the midline

A

Robo encodes cell surface receptor for Slit (repellant)
Robo prevents crossing the midline

Comm encodes a trafficking protein that prevents Robo protein reaching cell surface
Therefore, Comm allows crossing

*In Robo mutants, Slit no longer detected, so axons go back and forth (roundabout) the midline
In Comm mutants, axons cannot cross midline so extend their axons longitudinally

33
Q

What controls whether follower axons stay on the axon scaffold?

A

Fasciclin II controls fasciculation and defasciculation
Involves “homophilic” binding by cell adhesion molecules (CAMs)
BEAT interferes with CAM-mediated adhesion

*Fas II mutants have many defasciculated axons
Overexpression of Fas II leads to “by-pass” phenotype where axons fail to defasciculate so miss their targets

34
Q

Explain the two types of target selection

A
  • Discrete targets
    e. g. insect muscles express netrin and Fasciclin 3 that constitute muscle ‘address label’ for axons
  • Topographic Maps
    Ephrins A2 and A5 expressed in gradient (high in posterior tectum, low in posterior tectum)
    Eph receptor expressed in counter gradient (high in temporal, low in nasal)
    Therefore, temporal axons grow to anterior tectum and nasal axons grow to posterior tectum
35
Q

Cell death pathways, regulated by neurotrophic factors are critical for:

A
  1. Size matching of tissue to numbers of innervating neurons
  2. Removal of transient structures
    • Transient neuronal populations (e.g subplate/Ti1)
    • Transient cellular structures (e.g. neurite pruning)
36
Q

What are dependence receptors?

A

These are receptors that promote cell survival and proliferation when bound but promote cell death in the absence of a ligand
TrkA (Hi affinity) when bound, internalises and activates
- MAP kinase pathway to upregulate proliferation and differentiation
- Akt pathway to inhibit apoptosis and promote cell movement
- Can influence synapse formation

p75-NTR (Lo affinity)

37
Q

Describe dependence of neuronal populations on distinct combinations of neurotrophic factors

A

NT3 and BDNF support neuronal types early in development

Then as target reached, NGF and MSP (Macrophage Stimulating Protein)

38
Q

What is seen at sites of fragmentation in NGF-deprived sensory axons?

A

Caspase 6 activation by Amyloid Precursor Protein (APP)
Caspase 6 binds to Death Receptor 6 and initiates programmed cell death

*APP is implicated in Alzheimer’s so this pathway is a good target for neurodegenerative disease therapies

39
Q

What controls receptor clustering in synapse formation?

A

Agrin is a secreted ECM protein made by motor neurons
It binds to MuSK (Muscle-Specific Kinase) which auto phosphorylates and recruits Rapsyn which recruits and clusters AchR
Ach is also released and activates AchR
When Ach activity is not paired with agrin signalling, it inhibits AchR expression
Muscle depolarisation suppresses AchR mRNA and increases AchR protein degradation

40
Q

Explain the action of neurexins and neuroligins

A

Neurexins are presynaptic ligands and neuroligins are postsynaptic receptors
They allow spatial segregation of different inputs/ outputs e.g. separated innervation by excitatory/ inhibitory inputs

*Contacts between dendrite and axon triggers intracellular Ca2+ signalling
This promotes scaffolding proteins - CaSK (pre-synaptic) and PSD-95 (post-synaptic)

41
Q

Give an example of glia inducing pre-synaptic specialisation

A

RIA axons that form pharyngeal nerve ring are synapsed upon by AIY axons
Sheath (glia) cells secrete netrin (unc6) which guides RIA axons ventrally
Netrin also causes receptors to cluster in the AIY neurons

42
Q

Describe the action of TTX

A

Na+ channel blocker that increases the rate of synapse loss

43
Q

What are the reward and punishment mechanisms in synapse formation?

A

Addition of BDNF triggers synaptic potentiation (strengthening) and maturation through TrkB (“Reward”)
proBDNF suppresses transmission and causes axonal retraction via p75 NTR
Inhibition of matrix metalloproteinase (MMP) which converts proBDNF to BDNF prevents synapse strengthening

*BDNF contributes to LTP
proBDNF contributes to LTD

44
Q

Describe LTP and LTD

A

High frequency stimulation of presynaptic cell results in long-lasting increased post-synaptic response (EPSP): Long Term Potentiation (LTP)

Low frequency stimulation of pre-synaptic cell results in long lasting decreased post synaptic response: Long Term Depression (LTD)

Hippocampal pre-synaptic neurons release glutamate when stimulated
Depolarising levels of Na+ flow through AMPAr in response to glutamate release, this unblocks NMDAr channels releasing a Ca2+ into the cell

45
Q

Motor neurons innervating the triceps and pectoral muscles develop monosynaptic connections directly with proprioceptive Ia sensory neurons, whereas MNs innervating the cutaneous maximus and latissimus dorsi receive polysynaptic input from interneurons

How is polysynaptic input achieved?

A

GDNF is secreted from CM and LD which turns on Pea3 to give polysynaptic identity

46
Q

Give an example of how circuit completion relies on NT3 target feedback

A

NT3 induces expression of TF Er81 by Ia proprioceptors - essential for development of central projection to ventral horn

47
Q

A cell that does not require sensory input to differentiate is….

A

Merkel cells

48
Q

What are some examples of functional property maturation?

A
  • Sweat gland motor inputs change from being noradrenergic to cholinergic as glands mature and change function
  • Action potentials early on are generated by Ca2+ flow, not Na+ which appears later due to changes in ion channel subunits being expressed
  • GABAa receptors can switch from driving outward (excitatory) to inward (inhibitory) Cl- currents
49
Q

What is the difference in Peripheral and Central Nerve Regeneration?

A

Peripheral Nerve Regeneration
If peripheral nerve crushed or severed
- proximal axon and soma reorganise and re-express immature features
- distal axon undergoing Wallerian degeneration
- Schwann cells undergo mitosis and form bands of Bungner
- Axons regrow along bands
- Sporuting

Central Nerve Regeneration

  • Recovery of connections is difficult
  • Myelin protein Nogo-a inhibits axon growth in the CNS
50
Q

What part of the vertebrate CNS does regenerate?

A

The eye - optic cup

  • Inner layer contains retinal stem cells called neuroblasts that give rise to ganglion cells
  • Produce ventricular progenitors in layers
  • Outer layer : stem and progenitor cells give rise to retinal pigment epithelium
  • Lens stem cells give rise to ‘lens’ cell - which throws out nucleus and produces crystallin

DEVELOPMENTAL NEUROBIOLOGY (1 decks)

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