The WAVE complex in developmental and adulthood brain disorders

Abstract

Actin polymerization and depolymerization are fundamental cellular processes required not only for the embryonic and postnatal development of the brain but also for the maintenance of neuronal plasticity and survival in the adult and aging brain. The orchestrated organization of actin filaments is controlled by various actin regulatory proteins. Wiskott‒Aldrich syndrome protein-family verprolin-homologous protein (WAVE) members are key activators of ARP2/3 complex-mediated actin polymerization. WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1. The activity of the WAVE complex is tightly regulated by extracellular cues and intracellular signaling to execute its roles in specific intracellular events in brain cells. Notably, dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders. De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder. In addition, alterations in the WAVE complex are implicated in the pathophysiology of Alzheimer's disease and Parkinson's disease, as well as in behavioral adaptations to psychostimulants or maladaptive feeding.

Fig. 1. Expression pattern of subunit paralogs of the WAVE complex.

a Scatter plot of single-cell RNA-seq data for single cells isolated from the whole hippocampus and cortex (left panel). The glutamatergic, GABAergic, and non-neuronal cell types corresponding to the segregated cells are indicated (right panel). Publicly available single-cell RNA-seq data for WAVE genes: Wasf1, 2 and 3 (b), Abi1, 2 and 3 (c), Cyfip1 and 2 (d), Nckap1 and 1l (e) and Brk1 (f). Allen Institute for Brain Science (https://portal.brain-map.org/atlases-and-data/rnaseq).

Fig. 2. A proposed model for various input signals and regulators converging on the WAVE complex, leading to ARP2/3 complex-mediated actin polymerization.

Constitutively active kinases (CDK5 and CK2) basally phosphorylate WAVE, and the intramolecular interaction of the WCA domain with the meander region in WAVE inhibits actin polymerization. In contrast, activated neurotransmitter, growth factor or steroid hormone receptors and their signaling pathways may activate various regulators of the WAVE complex, including direct activators (such as RAC, ARF and PIPn), protein kinases or phosphatases that modulate phosphorylation levels in the WAVE complex, and protein interactors that localize the WAVE complex at locally active sites. WIRS-containing cell adhesion molecules or receptors recruit the WAVE complex to cell membranes. The integration of such input signals results in spatially and temporally orchestrated ARP2/3-mediated actin polymerization in a variety of cellular events. This figure was created with BioRender.com.

Fig. 3. Regulation of the WAVE complex by phosphorylation.

Phosphorylation at multiple sites on WAVE (a–c) and ABI1 (d) is regulated by protein kinases or protein phosphatases. The proposed roles of phosphorylation (stimulatory as blue, inhibitory as red, and uncharacterized as black) are indicated. The phosphorylation sites are illustrated for human sequences. WHD WAVE homology domain, B basic domain, PRR proline-rich region, WCA WASP homology 2 (WH2), central, acidic domain, WAB WAVE-binding domain, SNARE soluble N-ethylmaleimide-sensitive factor-activating protein receptor domain, HHR Hox homology region, SR serine/threonine-rich region, PP polyproline region, SH3 Src homology 3 domain.

Fig. 4. The WAVE complex mediates various cellular events, and alterations in the WAVE complex are associated with brain disorders.

a Subunit proteins in the WAVE complex are known to be involved in specific cellular events. b Alterations (blue box) in specific subunit proteins in the WAVE complex are associated with the pathophysiology (yellow box) of NDDs, AD, PD, cocaine reward and binge eating behavior. This figure was created with BioRender.com.