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  • Review Article
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Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis

Nature Reviews Neuroscience volume 3, pages 694–704 (2002)Cite this article

Key Points

  • The sprouting and elongation of axons and dendrites forms the basis of correct neuronal connectivity and brain function. The initial sprouting of a neurite is a three step process — the original round shape of the cell is broken down to make a bud, the bud is transformed into a neurite, then the neurite is transformed into an axon or dendrite.

  • The basic engine that generates the force required for neurite extension is thought to be the actin cytoskeleton, although membrane addition and microtubules are also important for the maintenance of the elongated neurite, its polarity and its speed of growth.

  • The morphology and orientation of early neurites reflect the nature of the molecules in the surrounding environment. This review focuses on the integrin–laminin complex to illustrate the role of the external world in the initiation of neuronal differentiation.

  • Integrin receptor activation produces a membrane change that results in neurite protrusion, indicating that the making of a neurite might be determined by the presence of discrete microdomains or 'hot spots' on the plasma membrane.

  • An early sign of the contact between the neuronal membrane and an extracellular ligand is a change in membrane appearance, from an even surface to one that is ornamented with veils (lamellipodia) and spikes (filopodia). This is preceded by the formation of thin membrane tethers that are mobilized from internal membrane stores. Localized addition of new membrane through the exocytotic pathway might account for the stabilization of lamellipodia and filopodia into real neurites.

  • Neurite protrusion requires the actin cytoskeleton, and high or low actin turnover seem to form the basis of neurite outgrowth or quiescence, respectively. Studies in fibroblasts and budding yeast have shown that actin-based motility is regulated by the Rho family of GTPases, and there is strong evidence that a similar mechanism operates in neurons.

  • Stimulation of certain receptors causes Rho proteins to undergo changes in activity, which lead to the formation of multimolecular complexes that can induce actin remodelling and cell movement. These complexes contain not only the Rhos and their regulatory proteins, but also actin-binding molecules and scaffold proteins, including the formins.

  • The microtubule cytoskeleton is another postulated target of Rho GTPases, and protrusion of microtubules into newly formed neurites seems to be required to sustain their development and elongation.

  • Mutations that affect neurite extension cause neurological diseases in humans that range from varying degrees of mental retardation to severe heterotopias. Understanding the secrets behind the conversion of a spherical neuronal-precursor cell into a fully differentiated neuron might lead to better approaches to treat these disorders.

Abstract

The sprouting of neurites, which will later become axons and dendrites, is an important event in early neuronal differentiation. Studies in living neurons indicate that neuritogenesis begins immediately after neuronal commitment, with the activation of membrane receptors by extracellular cues. These receptors activate intracellular cascades that trigger changes in the actin cytoskeleton, which promote the initial breakdown of symmetry. Then, through the regulation of gene transcription, and of microtubule and membrane dynamics, the newly formed neurite becomes stabilized. A key challenge is to define the molecular machinery that regulates the actin cytoskeleton during initial neurite sprouting. We propose that analysing the molecules involved in actin-dependent mechanisms in non-neuronal systems, such as budding yeast and migrating fibroblasts, could help to uncover the secrets of neuritogenesis.

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Figure 1: Initial steps of neurite formation.
Figure 2: Formation or activation of membrane microdomains.
Figure 3: Simplified view of the action of Rho proteins in fibroblasts and neurons.
Figure 4: Role of actin-related proteins in neurite formation and extension.

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Acknowledgements

We thank all the members of the laboratory for their contribution to this work through helpful suggestions and insightful comments on the manuscript. J.S.S. is supported by an FCT/PRAXIS XXI scholarship (Portuguese Ministry of Science and Technology).

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Authors and Affiliations

  1. Cavalieri Ottolenghi Scientific Institute, Universita Degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10024, (Torino), Italy

    Jorge Santos Da Silva & Carlos G. Dotti

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  1. Jorge Santos Da Silva
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  2. Carlos G. Dotti
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Correspondence to Carlos G. Dotti.

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DATABASES

FlyBase

Bazooka

Cappuccino

Chickadee

Diaphanous

Inscuteable

Numb

Prospero

LocusLink

α-actinin

ADF

Arp2

Arp3

Cdc42

cofilin

collagen

FGF2

FGF7

filamin

gelsolin

HB-GAM

IGF

laminin

mDia

Mena

neurotrophins

profilin

Rac1

RhoA

ROCK

Slit

tenascins

TGF-β

thymosin-β4

VASP

VEGF

WASP

<i>Saccharomyces</i> Genome Database

Bee1p

Bem1p

Bni1p

Bnr1p

Bud1p

Bud2p

Bud5p

Cdc24p

Cdc42p

COF1

Myo1p

Rho1p

Rho2p

Rho3p

Rho4p

WormBase

INA-1

FURTHER INFORMATION

Encyclopedia of Life Sciences

actin and actin filaments

axon growth

axonal transport and the neuronal cytoskeleton

cytoskeleton

Glossary

LAMELLIPODIUM

A sheet-like extension at the edge of cells that contains a crosslinked F-actin meshwork and is often associated with cell migration.

FILOPODIUM

A long, thin protrusion at the periphery of cells and growth cones that is composed of F-actin bundles.

LATERAL GANGLIONIC EMINENCE

A region of the embryonic brain that gives rise to the striatum. It is also the source of a population of cells that migrate to populate the cerebral cortex and the olfactory bulb.

DII

DiI is a lipophilic carbocyanine dye that emits an intense fluorescence when incorporated into cell membranes. It is commonly used to track cell migration, or for the retrograde or anterograde tracing of axons. It can be used on both live and fixed tissue.

HETEROTOPIA

In general, this terms refers to the displacement of neuronal cell bodies into the white matter.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

DOMINANT NEGATIVE

Describes a mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

STRESS FIBRES

Bundles of microfilaments and other proteins that are commonly found on migrating cells. They are contractile and can be anchored to a focal adhesion.

FOCAL ADHESION

An area of close apposition between the membrane of a cell and the surface along which the cell is moving.

SH DOMAINS

Src-homology domains are involved in interactions with phosphorylated tyrosine residues on other proteins (SH2 domains) or with proline-rich sections of other proteins (SH3 domains).

ADP RIBOSYLATION

The transfer, through an ADP ribosyltransferase, of one or more ADP-ribosyl groups from NAD+ to a protein.

PC12 CELLS

Neuron-like cells that are derived from a malignant neural crest tumour (a phaeochromocytoma).

N1E-115 CELLS

An adrenergic cell line derived from a mouse neuroblastoma that is commonly used in studies of tumorigenicity.

TOXIN B

A glucosyltransferase that inhibits members of the Rho family of GTPases. It is produced by Clostridium difficile, the causative agent of pseudomembranous colitis.

POINTED END

The structural polarity of filamentous actin was defined by decoration with myosin fragments. This procedure resulted in an arrowhead appearance of the actin filament, with a 'barbed' end and a 'pointed' end. The addition of actin monomers is more favoured at the barbed end than at the pointed end.

CORTICAL MESHWORK

A submembranous layer of microfilaments anchored to the cell membrane that contributes to the mechanical properties of the cell surface and restricts the access of cytoplasmic vesicles to the plasma membrane.

SWISS 3T3 CELLS

An immortal line of fibroblast-like cells that was established from embryos of Swiss mice (which are not an inbred stock). They form confluent monolayers, and their mobility is highly inhibited by contact.

CYTOKINESIS

The final event in the cell-division cycle. Its completion results in the irreversible partition of a mother cell into two daughter cells. It involves cytoplasmic division, driven by an actin-based constriction of the contractile ring. It is worthwhile comparing cytokinesis with mitosis — the process of nuclear division.

RBD DOMAIN

Rho-GTP-binding domain. The RBD of the mammalian diaphanous proteins binds only activated RhoA–C, whereas diaphanous proteins of budding yeast interact with Cdc42 as well. The binding of activated Rho to the RBD of diaphanous proteins stimulates actin reorganization.

CIID DOMAIN

C-terminal intramolecular domain of diaphanous proteins. The RBD domain complexes with CIID in a species-restricted manner to autoregulate the activity of diaphanous proteins.

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Da Silva, J., Dotti, C. Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis. Nat Rev Neurosci 3, 694–704 (2002). https://doi.org/10.1038/nrn918

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