Development Flashcards
(23 cards)
What are the 4 stages of embreyonic development of the spinal cord?
- Neural plate - cotains the notochord, developing somites and epidermal ectoderm. Sonic Hedgehog produces by notochord and BMPS released by neural plate calls
- Neural fold - structure folds up and contains floor plate which now also produces Shh
- Neural tube - tubular structure which also develops a roof plate and the neural crest cells which go on to form the dorsal root ganglion
- Spinal cord - various developing neuroons including motor neurons, dorsal root ganglion (snesory input) and commisural interneurons
What is sonic hedgehog?
- Ventralising agent
- Produced by notocord and floor plate to produce a concentration gradient (ventral - high, dorsal - low)
- Acts as morphogen, position of progenitor cells within dorsal to ventral gradients determines differentiation into specific subtypes
What are transcription factors (homeodomain proteins)?
- Expressed within progenitor domains and interpret Shh gradient
- Protein which regulates binding of RNA polymerase and initiation of transcription. Binds upstream to repress or enhance transmission
- In spinal cord these are known as homeodomain proteins (part which can bind to DNA)
What are the two classes of homeodomain proteins involved in Shh signalling?
Class I - Expression is repressed by Shh ventral boundaries of expression delineate progenitor domains Class II - expression is induced by Shh dorsal boundaries delineate progenitor domains Cross repression between complementary class I and II homeodomain proteins defines dorsoventral progenitor domains ensuring sharp boundaries and relieving the requirement for ongoing Shh signalling
How is the dorsal-ventral axis specified? How do motor neurons develop from this?
- Graded activity of Shh (ventral to dorsal) activates class I factors and represses class II factors, with cross repressive interactions sharpening boundaries
- This defines the progenitor cells, progenitors of motor neurons depend on the specific transcription factors Nkx6, Olig2 and Pax6
- These then divide with postmitotic cells expressing these homeodomain proteins: Hb9, Ils1/2 and Lhx3/4, gaining generic MN characteristics such as projection of axons outside the spinal cord and ACh signalling
What is the layout of the spinal cord?
3 sections - brachial, thoratic and lumbar
What is the medial motor column?
- Present in the length of the spinal cord
- Innervate axial muscles
- Express the transcription factors OCT-6/SCIP-1 and LHX3
What is the lateral motor column?
- present in brachial and lumbar level, innervate the limb muscles
- Express Foxp1 and Lhx1/2
- Two categories - medial lateral motor column with axons project ventrally within the limb innervating flexors and lateral lateral motor column with axons which project dorsally to extensors
What are lim codes?
- Expressed at final stage of division as well as post-mitotically in motor neurons
- Define sections of the spinal cord
How does LIM code expression change during development?
- During conception all MNs express Isl-1 and Isl-2
- At time of axon extension MMC neurons express Isl-1, Isl-2, and Lim-3
- Axons innvervating ventral limb muscles Isl-1 and Isl-2
- Axons innervating dorsal limb muscles s Lim-1 and Isl-2
How do non-medial motor column neurons develop?
Cell body settling laterally or dorsally with expression of lsl1/2(+/-) and Llm1(+/-)
What role does graded wnt4/5 expression play in motor neuron development?
- Control LIM code
- Wnt(4/5a/5b) expressed around the flor plate producing ventral-dorsal gradient and controlling Lhx3/4 expression
- Wnt4/5 promotes MMC by maintaining Lhx3/4expression
- reducing Wnt4/5 activity in mice promotes the generation of HMC neurons at the expense of MMC neurons
What role does FGF and Hox codes play in MN identity?
- Fibroblast growth factor (FGF) expressed in rostrocaudal gradient
- Hox genes interpret this gradient, with different Hox genes turned on according to concentration
- Combination of hox genes allows for different segmental motorneuron types to be expressed
- Cross repression defines boundaries
What role do neurotrophic factors play in motorneuron development?
- Neurotrophic theory : populations of developing neurons compete during their period of programmed cell death for limiting amounts of target-derived neurotrophic factors (NTFs), which determines their
survival or elimination - Over 15 identified to act on motor neurons, and believed to act in combination (in mice, knockout of one does not produce much of an effect where as genetic ablation of cell types releasing multiple (e.g muscles of schwann cells) leads to almost complete motor neuron loss)
What is the Preganglionic column?
Found in the thoracic motor column, produces preganglionic motor neurons of the sympathetic and parasympathetic nervous system ensure the innervation of ganglionic neurons and express low levels of Foxp1
What specific neurotrophic effects have been observed with specific motor columns?
Schaller (2017)
- Using isolated spinal cord neurons from mice
- HGF and ARTN supported survival of LMC/PGC neurons but not MMC (coupled with preferential response to these proteins (upregulation of receptors) by these mtoro columns)
- CNTF supported survival of MMC with no significant effect on others
Describe the process by which the dorsoventral axis of the forelimb is defined
1) convergent activity of Shh (D-V) and FGF (R-C) producing hox6 results in the expression of Foxp1 and RALDH2 providing a source of retanoic acid. This then induces Lhx1 signalling and expression of guidance receptor EphA4 directing motor axons towards the dorsal limb
How can Hox signalling result in motor pools of different sizes?
- Initially a motor pool will inherit multiple Hox genes as a function of R-C position
- This is then refined through cross-repressive interactions which makes pool cluster with different sizes of pools resulting from differing strengths of repression
Which Hox signals are expressed at different motor columns?
- Hox4-8 at brachial
- Hox 8-9 at thoracic and Hox 10- Hox 11 at lumbar
What is the current way in which the LMC and PGC have been believed to arise?
- Ancestral fish moved through axial movements and so had MMC and HMC (without Lhx3)
- Removal of Lhx3 produced malleable population which was then responsive to Foxp1 signalling through does dependent indusive activity
- resolve their bi-potential HMC or PGC fate through mutual repressive interactions between FoxP1 and Hb9 according to Hox programme
Give an example of how hox dependent signalling has underlied evolutionary changes
In snakes, which evolved from limbed tetrapods, extension of Hoxc9 expression into more rostral
segments leads to a repression of the forelimb MN
Hox network and a loss of LMC neurons at cervical levels
How do patterns of limb pool innervation change with position?
Pools located more rostrally tend to innervate muscles located rostral and proximal within the limb, while caudal pools project to more caudal and distal regions
At which stages of development are the different programs of transcriptional cross-repression active?
- Shh gradient defining dorsal-ventral axis in progenitor cells
- FGF gradient establishing rostral-caudal graident: post-mitotically
