22 – Nervous system 2: Guidance & Migration Flashcards
what we need to set up a proper nervous system?
Proper wiring = Right neurons making the right connections
Wiring the Brain isn’t easy!
Problem #1: Making the Right connections
o Stage 1: immature neuron
o Stage 2: immature neurite starts growing
o Stage 3: one of immature neurite start growing as Growth Cone
o Stage 4: growth cone become axon; another immature neurite become dendrite
o Stage 5: Axon dendrite start branching & dendrite become dendritic spine
Problem #2: Getting neurons to the right place
Neurons migrate long distances to pattern the cortex
Neurons migrate radially to pattern the cerebral cortex
* 1. Growth cones extend
* 2. Cell body moves forward
During brain development – axon MUST
extend to reach the right target
Leading process of axons
- Axons = lead by growth cones
- Leading process = growth-cone like
Growth cones contain…
contain complex cytoskeleton machinery
Microtubule role in…
role in neuronal migration
how do we know microtubule is important?
Mutation in Doublecortin (DCX) – cause defects ion neuronal migration
-caused by single aa substitution
-DC1 & DC21 make DCX
DCX-KO iNEurons
have excessive branching phenotype of DCX & Tubulin
-Show reduced migration & nuclear movements
-Change in polyglutamylation (promotes/inhibits severing & control MAPs binding)
There are less of polyglutamylation in DCXKO
Why would a mutation in a microtubule associated protein make
it such that your neurons don’t migrate?
the scratch assay
Depolymerization of microtubules = stops migration in scratch assay
Without microtubules = lamellipodia extend BUT go nowhere
Unable to know directions
Lamellipodia everywhere=goes everywhere
-doesnt know which is front/back
Microtubule depolymerization in non-migrating cells … & why?
induce stress fibers
hypothesis:
-Microtubules = alter activation state of Rho family GTPases
—Get rid of microtubules = Rho active
-Microtubules must activate Rac & inhibit Rho At leading edge
Cdc42 + GTP filopodia formation
Rac + GTP = lamellipodia formation
Rho + GTP = stress fiber formation & contraction
without the microtubules the the actin
actin does notknow how to polarize.
The the actin system cannot find which way is up and instead the cells migrate randomly around.
link between the behavior of microtubules and these upstream actin regulatory proteins?
Pioneer microtubules = penetrate into lamellipodia & filopodia
Growing microtubules = activate Rac & inhibit Rho
Microtubules – sequester & inactivate a Rho-GEF (hold on to microtubule & kept in inactive state)
explains why when you de polymerize
microtubules, you would get stress fiber formation.
You get rid of your microtubules, this Rho GEF gets released into the cytoplasm, it switches row into the active state and now you start to get stress fiber formation every which way.
Tubulin code
information system for microtubule specialization
o Detyrosination
o Tyrosination
o Acetylation
o polyglutamylation
Growth cones = attracted to some guidance cues & repelled by others:
example & experiment with mive lacking it:
Netrins = can attract some growth cones & repel others
Mice lacking netrin = show defective spinal cord organization
-Defective ventral midline & floorplate
how does the neurons find their destination?
brain establish gradients of signaling molecules, both attractive and repulsive signaling molecules.
And gradients of signaling molecules help steer the neuron to its final destination.
Guidance cues connect to
Rho family GTPases
Guidance cues
attract growth cones
