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Developmental Neurobiology > Generation and regeneration of Motor Neurons > Flashcards

Generation and regeneration of Motor Neurons Flashcards

1
Q

where are MNs located in the CNS

A

HB
ventral horn of SC

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2
Q

what is local processing

A

activation of the flexor muscle inhibits the extensor muscle (antagonistic muscle)

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3
Q

where is Shh produced

A

floorplate and notochord

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4
Q

MN production

A

neural progenitor domain pMN in the ventral neural tube

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5
Q

Class I/II TF

A

class I TFs (Pax6/Dbx2) repressed by Shh
Class II TFs (Nkx2.2/Nkx6.1) activated by Shh

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6
Q

Evidence to show graded Shh signalling

Ericson et al., 1997

A

Titration of Shh forms different neuronal subtypes:
V1 - low conc
V2 - intermediate conc
MN - high conc of Shh

use reverse anti-Shh antibody - Shh conc is 0 (no V1/V2/MN)

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7
Q

motor column

A

PGC (FoxP1 low)
LMC (FoxP1 high)
MMC (Lhx3)
HMC

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8
Q

sub column

A

LMCl (projects to dorsal limb)
LMCm (projects to ventral limb)

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9
Q

motor pool

A

rf-MP (Lhx1)
vasti-MP (Lsl1)

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10
Q

role of Hox genes

A

conserved
determine positional identity of cell types along the rostral caudal axis
males have 4 hox clusters
females have 1 hox cluster

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11
Q

Hox gene cluster

A

secondary organising centres along the R-C axis
morphogens which induce Hox genes: Gdf11, RA, FGF

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12
Q

FGF manipulation in chick/mammals using electroporation

A

FGF8 causes gain of Hoxc9/loss of hoxc6

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13
Q

LMCm/LMCl projections

A

LMC m project to ventral limb contains ephrin A TF: Isl1 Receptor: EphB
LMC l project to dorsal limb contains ephrin B TF: Lhx Receptor: EphA

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14
Q

ectopically expressing LMCl/m determinants

A

GFP (control) 50/50 projection to d/v limb
GFP+lim1 (LMC l) - most projections to dorsal limb
GFP+Isl1 - mostly ventral projections

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15
Q

role of Pea3

A

marks 2 motor pools in LMC m

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16
Q

dendritic morphology of Pea3/non-Pea3 pool

A

Pea3 pool - cresent shaped, no sensory axons, no medial projections
non-pea3 pool: project medially

17
Q

pluripotent embryonic stem cells

A

derived from inner cell mass
forms all germ layers

18
Q

in-vitro formation of MN from embryonic stem cells

A

express morphogens: RA/Shh (provide positional information)

19
Q

ectoderm to MN formation

A

primative ectoderm - rostral neural - via RA - caudal neural - via Shh - MN

neural induction/caudalisation/ventralisation

20
Q

what do ES derived MNs form

A

MMC
HMC
not PGC (controls involuntary movement)

21
Q

role of doxycycline

A

chemical on/off switch
induces TFs: Ngn2/Isl1/Lhx3
produces transcriptional profile of NIL motor neurons generated by extrinsic factors (RA/shh)

22
Q

NIP vs NIL

A

NIP - exist dorsally, cranial MN
NIL - exist ventrally spinal MN

23
Q

NIL MN

A

express all markers of somatic MNs derived with extrinsic factors but lack expression of progenitor specific genes (Sox1/olig1/olig2)
transition from early embryonic identity to post mitotic MN (skip neural progenitor stage)

24
Q

generation of induced MNs

A

mouse embryonic fibroblasts (MEFs) - expose to late progenitors (sox1/Pax6/Nkx6.1/Olig2) - MN+glia

25
Q

application of induced MNs

A

ALS patient fibroblast - direct conversion to MN (respond to chemicals) form NMJ

26
Q

amyotrophic lateral sclerosis

A

selective degeneration of MNs/neurons of the motor cortex - progress muscle weakness and spasticity (most of CNS unaffected)
risk of development: 1in 500
death of patient: 3-5 yrs after onset of symptoms (lose innervation of respiratory muscles)
no effective treatment
10-15% genetic cause
most commonly: defect of superoxidase dimutase 1 (SOD1) point mutation
sporadic ALS is usually polygenic

27
Q

mutant SOD1

A

extract SOD1 from astrocytes - coexpress with hESC MN - Hb9/GFP+ cells
astro SOD1 mutant - degeneration of MNs

28
Q

use of co-cultured astrocytes and MNs

A

ALS drug screening

29
Q

limitation of induced MN

A

optogenetic activation of MN (blue light on ChR) replace input from spinal circuits
do not reflect normal MN pathology

30
Q

in-vitro neuromuscular circuits

Osaki et al., 2018

A

develop in-vitro NM device using human iPSC MN (form NMJs with myofibers) - stabilised by 2 flexible pillars

in ALS, MN fail to induce myofiber contractions when stimulated with light

Developmental Neurobiology (19 decks)

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