WRP/srGAP3Facilitates the Initiation of Spine Development by an Inverse F-BAR Domain, and Its Loss Impairs Long-Term Memory

Abstract

The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show that this domain senses/facilitates outward protrusions analogous to filopodia and that the molecular basis for this is likely explained by a convex lipid-binding surface on the WRP IF-BAR domain. In dendrites the IF-BAR domain of WRP forms a bud on the shaft from which precursors to spines emerge. Loss of WRP in vivo and in vitro results in reduced density of spines. In vivo this is primarily a loss of mushroom-shaped spines. Developmentally, WRP function is critical at the onset of spinogenesis, when dendritic filopodia are prevalent. Finally, because WRP is implicated in mental retardation, behaviors of WRP heterozygous and null mice have been evaluated. Results from these studies confirm that loss of WRP is linked to impaired learning and memory.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Knocking out SrGAP3 decreases the number of dendritic filopodia in early development, and it is therefore plausible that SRGAP3 deficiency also leads to decreased dendritic spine density in human patients 255 . Two de novo missense variants in the SRGAP3 gene (one predicted to be probably damaging, and the other predicted to be possibly damaging) were identified in ASD probands from the Simons Simplex Collection 118 .…”

Actin Out: Regulation of the Synaptic Cytoskeleton

“…7). Mutations in spine-enriched GEFs (for example, kalirin-7 (8)) and GAPs (for example, WAVE-associated Rac GAP (WRP) (9,10)) are associated with SZ and ID, implicating the local control of Rho family GTPase activity and actin remodeling in essential spine functions (Fig. 3).…”

“…These filopodia are understudied, highly transient structures that emerge from dendrites before spinogenesis (around day 9 in vitro in cultured hippocampal neurons) (9). They lack the rounded spine head and are thought to serve as the first contact sites between nascent axonal boutons and dendrites during the development of the synapse.…”

A-kinase Anchoring Protein 79/150 Recruits Protein Kinase C to Phosphorylate Roundabout Receptors

“…For example, the AKAP WAVE1 is expressed at the leading edge of growth cones, where it controls actin dynamics to facilitate axonal protrusions (63)(64)(65)(66). In addition, the Drosophila anchoring protein Nervy coordinates signaling at the plexin family of semaphorin receptors (67).…”