NEUS 609 - Axonal Growth & Guidance I

somatodendritic domain

made of receptive field (dendrites) of neuron and the cell body

axonal domain

transmitting domain of neuron

initial segment, axon hillock

the segregation between somatodendritic and axonal domains is maintained by the axon ___ and the ___.

axon growth stages

1. veil-like lamellipodium symmetrical extension

2. lamellipodium condenses to form short equivalent (same potential) processes aka neurites

3. one process stats to grow rapidly and become axon

4. remaining neurites become dendrites

Par proteins

___ are required for axonal specification

Diverse set of kinases and scaffolding proteins that form a complex at the site of initiation

• if mutated, all neurites would have axonal characteristic, making nerve cell more symmetrical and non-functional. Fatal mutation.

microtubule extension, microfilament remodeling

NGF and TGFB activate the Par proteins, which then activate either PI3 kinase leading to _____, OR activate Rac1 and Cdc452 leading to ____.

GSK3B, CRMP2

microtubule extension is regulated by ___ (glycogen synthase kinase), and ___ (collapsing response mediator protein)

growth cone

leading end of a growing process; sensorimotor structure that guides and propel the growing process

• present in both axon and dendrites

• idea presented by Ramon y Cajal in 1890

• possesses motive force and chemical sensitivity

central domain

center of growth cone containing membrane vesicles and organelles as well as stable (acetylated or de-tyrosinated) microtubules

peripheral domain

borders of growth cone made of filopodia and lamellipodia; contains dynamic (tyrosinated) microtubules

filopodia

finger-like structures; microfilaments arranged in tight, radial bundles

lamellipodia

microfilament loose network made of dynamic (tyrosinated) microtubules

intrinsic

growth cone requires a highly dynamic cytoskeleton as movement is ___ to the growth cone

• not dependent on connection to cell soma

actin-associated proteins

regulates microfilament polymerization and depolymerization

• profilin

• capping proteins

• Apr 2/3

• fimbrin

• ADF/cofilin/gelsolin

profilin

binds monomeric actin and facilitates addition to the growing + end

fimbrin

causes cross-linking/bundling of microfilaments

Apr 2/3

promotes microfilament branching

ADF/cofilin/gelsolin

causes microfilament severing

capping proteins

stops microfilament elongation

Rho GTPases

actin associated proteins are regulated by the ___ family of enzymes

active

RhoGTPases are __ when bound to GTP

inactive

RhoGTPases are ___ when bound to GDP

guanine exchange factors

___ (GEFs) are allowing RhoGTPases to oscillate between active and inactive forms

Rac

RhoGTPase favoring elongation in filipodia

Cdc452

RhoGTPase favoring elongation in lamellipodia

Rho

RhoGTPase favoring collapsing of microfilaments

growth factor, cytokines, or adhesion molecules

actin-associated proteins are regulated by RhoGTPases, which are activated by GEFs, which are regulated by receptors activated by ___, ___, or ___.

stationary/treadmilling

amount of polymerization equals amount of depolymerization

• microfilaments bound to myosin which is anchored in plasma membrane

retraction/collapse

polymerization is less than depolymerization

• also involve action of cofilin

• microfilaments shorten but are still bound to myosin

extension

polymerization is more than depolymerization

• require clutch

• force of myosin stroke is converted into rapid forward movement through its attachment to plasma membrane

• further elongation due to thrust of microtubules in central domain

clutch

protein complex linking microfilaments to membrane-bound adhesion molecules, which bonds to the extracellular environment

• directly link to substratum aka extracellular matrix (EMX)