The Arp2/3 complex is essential at multiple stages of neural development

Abstract

During development of the nervous system, radial glial cells perform self-renewing asymmetric divisions and give rise to intermediate progenitor cells (IPC) and neurons. The neuronally committed IPC subsequently undergo multiple rounds of transient amplification and migrate outwards to form cortical layers as they continue to differentiate into mature neurons. Maturing neurons extend protrusions on their cell surface to form neurites, a process called neuritogenesis. Neurite formation results in the establishment of dendrites and axons for synapse formation, which is essential for sensory and motor functions and even higher-level functioning including memory formation and cognitive function, as well as shaping of behavior and emotion. Morphological adaptation during various stages of neural development requires active participation of actin cytoskeleton remodeling. In this review, we aim to discuss current understanding of the Arp2/3 complex branching nucleator in various neural cell types during development and maturation.

Keywords: Arp2/3; actin cytoskeleton; neuritogenesis; neurogenesis; neuronal migration; radial glia.

Figure 1.

Representation of normal cortical lamination during cortical development (A) and following Arpc2 depletion (B). (A) On the apical side, short apical processes form end-feet that are attached to the ventricular surface. The end-feet between radial glial cells (RGC) are anchored to each other via cadherin-containing adherens junctions (AJ).The cell bodies of the RGC are normally located close to the ventricular surface. An elongated basal process extends radially from the cell body in the opposite direction of the apical end-foot and spans the entire progressively thickening cortex until it is in contact with the basal surface. Of note, the basal process is a dynamic structure. Cell division occurs by the apical surface. The Arp2/3 complex is present throughout the RGC, with enrichment in the apical end-feet and the growth cone-like structure at the tip of the basal process. (B) Following depletion of Arpc2, multiple defects in RGC end-feet and basal processes, as well as in neuronal migration, altogether lead to disorganized positioning of the RGC, the intermediate progenitors, and the maturing neurons throughout the cortex.

Figure 2.

Axonal growth cone structure. Three functionally distinct regions have been identified in the growth cone - the central (C) and the peripheral (P) domains, as well as the transitional (T) zone. The C domain is at the end of the axonal shaft where the microtubules extending from the axonal shaft terminate. The C domain are also rich in numerous organelles including mitochondria and exocytotic vesicles. The primary function of the C domain is to support the P domain, which consists primarily of actin cytoskeleton and has a dynamic morphology. In between the C and the P domains lies the T zone where microtubules interact with actin filaments through acto-myosin contractile structures. Filopodia-like finger protrusions at the P domain are supported by the lamellipodia-like web structures. This figure is adapted from Box 1 in Ref. .

Figure 3.

Synapse formation between dendrites and axons in the presence (A) and absence of Arp2/3 (B, C). (A) Dendritic spine with a mature-type morphology supported by actin cytoskeleton meshwork. Presynaptic axon is in contact with the dendritic spine. Postsynaptic receptors are supported by actin cytoskeleton on the plasma membrane. (B) Lack of dendritic spines in the absence of Arp2/3 complex. Presynaptic axon is in direct contact with the dendritic shaft. (C) Immature dendritic spines supported by filopodia-like protrusions with non-branching actin filaments in the absence of Arp2/3 complex lead to anomalous formation of double-axonal synapses. This figure is modified from Figure 4 in Ref. .