Lecture #7 Flashcards
what are hubs that allow neurons to make further selections to their direction?
intermediate targets
describe the growth cone:
a large structure that is composed of different cytoskeleton elements: the lamellar portion has a cortical actin ring and there are microtubules entering the central domain
what is the function of the actin in the growth cone?
essential to govern the attraction, repulsion, growth, and collapse of the growth cone
what does chemotropic mean?
there is a source that allows to move in that direction
describe the localization and activity of NGF:
released by specific targets an has guidance activity, because the polarized presence of this growth promoting molecule contributes to instruct guidance
in the simplest organisms, what is chemotaxis controlled through?
imposed by molecular systems abed on G proteins
in more complex organisms, what is chemotaxis controlled by?
tyrosine receptors - the ability to switch on and ff and fine tune the response is not something typically observed with G protein couples receptors
what are our neurons instructed by?
intermediate targets along the way
what re instructor molecules?
attractive and repulsive molecules that can often be secreted in the form of gradients or contact dependent interactions
what can the growth cone be compared to?
a GPS
what are the four canonical families of guidance molecules in the brain?
- ephrins (Eph receptor)
- semaphorins (Plexin / Nap receptor)
- netrin (DCC / Unc5)
- slit (ROBO recetor)
what are the three major properties of the receptors in the brain?
- they can act in short or long range
- they are multifunctional → same molecule can attract or repel depending on the context
- they are evolutionarily conserved
what is the function of the tip cell in blood vessels during development?
just like the growth cone, it extends the filopodia and expresses a lot of receptor for the guidance molecules to be also used by axons
what does a deterministic view of axon targeting mean?
you have a matching system ligand → the transcriptional identity of the different classes of neurons is linked to the expression of different receipts and therefore to a different connectivity
where are the commissural neurons of the spinal cord located?
sit at the dorsal part of the spinal cord and need to travel down with their axon to the floor plate, then cross it to reach the other side and continue to grow contro-laterally from the spinal cord to the brain
how do the commissural neurons know to cross the floor plate?
the floor plate secretes a chemotractant → netrin
what does the name netrin mean?
the one who guides
what does netrin resemble?
members of the laminin superfamily
where are netrins most often bound?
the ECM - they are secreted molecules but don’t go very far away
what is the main receptor used by netrin?
DCC whose activation by netrin activates an attractive response
how is repulsion with DCC triggered?
when DCC couples with a co-receotor called UNC-5 (uncoordinated)
triggers long range repulsion
what happens when UNC-5 is by itself?
it triggers short range repulsion
how does the floor plate use netrin to attract commissural axons?
the commissural axon expressed the attractive receptor DCC that sense the attractive netrin release by the floor plate in a gradient and this long range chemo-attraction guides the commissural neuron to the floor plate
where is netrin also released to help this guidance?
not only by the floor plate but is also released by the rip of radial glia the deposits netrin to the surface of the spinal cord
what two functions can a single ligand have?
can work to trigger chemotaxis on commissural axons but when bound to the surface, can also act as an adhesive molecule to promote growth
what happens when commissural axons see an attractive boundary of netrin deposited on the surface of the spinal cord?
they travel to it and use a haptotaxis mechanism that makes use of an adhesive substance to move
what is the ligand-receptor slit ROBO system?
a system of midline repulsion
where is slit located?
it is together with netrin in the midline
what is released if there is a commissural neuron that needs to remain ipsilateral (reaches the floor late but doesn’t need to cross it)?
ROBO is expressed so they are repelled
what type of neurons need to cross the floor plate?
contralateral neurons
what is expressed to allow contralateral neurons to cross the floor plate?
Comm: activate a protein degradation pathway, that when it is ON degrades ROBO so these neurons don’t sense the repellant and slit because they don’t have ROBO and only sense the attractant
what occurs to stop the crossing of contralateral neurons across the floor plate?
Comm is turned off so ROBO is expressed again, and now thee neurons become repelled by the presence of Slit
what animal expresses Comm?
drosophila
how do vertebrates turn on and off ROBO?
based on the expression of isoform Robo3 which antagonizes ROBO1 and 2, which are the ones which repel
what is the difference between drosophila and vertebrates in how they activate the repellant of ROBO?
drosophila: degrade the receptor
vertebrates: switch ON the isoform that antagonizes the activity of the repellant ROBO
what are the two main components for the receptor class of Semaphorins?
Nrp and Plexin
what is the most well-known class of Semaphorins?
class 3: uses Nrp to bind the receptor and uses plexus as co-receptors for transfusing the signal inside the cell
what do most semaphornins do?
create a corridor for axon growth
what is another class of semaphorins that can activate the reverse signaling (the ligand has a transmembrane domain that can transduce the signal)?
transmembrane semaphorins
describe class A ephins:
GPI encoded, they re exposed on the outside but lack a transmembrane domain
describe class B ephrins:
transmembrane proteins that are able to trigger both forward and reverse signaling
have both a transmembrane domain and a signaling domain
what is a topographic map?
a map where the position of the soma influences the targeting of the axon
where are secondary motor neurons located?
in the ventral portion of the spinal cord
what are unique abut secondary motor neurons?
they are the only CNS cells that are able to leave the CNS and grow to the target, which is usually in the muscles
how can the secondary motor neuron system be described?
hierarchal manner: if you disrupt the motor neuron track, then the sensory neurons don’t know where to go
describe the binary system of motor neurons:
there are two populations of motor neurons, they have different transcriptional identities and they decide once they reach the base whether to grow ventrally or dorsally
the choice point is at the base of the limb which is the intermediate target
what is important for the binary decision at the base of the limb in motor neurons?
ephrin
tyrosine kinase receptor EphA detects the continuous repulsive domain of ephrin A that is present in the ventral part of the limb
describe the backup system for the binary decision at the base of the limb in motor neurons:
the same axon that expresses ephA receptor also expresses the ephrin A molecule that can trigger the revere signaling which is attractive → both the axon and the target can express the ligand and the receptor
what happens when the axon reaches the base of the limb?
it is repelled by the ephrin domain expressed in the ventral domain and is pushed to the dorsal side
as it grows to the dorsal it is reinforced by the activation of this attractive-reverse signaling pathway that is activated by the continuous domain of EphA receptor that is present in the dorsal limb tissue
what happens in axonal growth once the receptor EhpA is turned on?
it activates a cascade that is able to modify the cytoskeleton
what are important switches of intracellular pathways in axonal growth?
Rho GTPases
what happens if RhoA is turned on?
disruption in the actin cytoskeleton
what two Rho GTPases help to form the actin cytoskeleton?
RAC1 and CD42
what is the activity of Rho GTPases set by?
the intracellular level of the second messenger
the ratio between which two second messengers can impose the responsiveness of the growth cone into different types of cues?
cAMP and cGMP
if you add netrin (attractant) but you lower the level of cAMP, the same ligand is no longer sensed as an attractant
if you take a repulsive molecule such as Sema3 and you increase the level of cGMP the repellant becomes an attractant
