Abstract
In the vertebrate central nervous system, exploratory filopodia transiently form on dendritic branches to sample the neuronal environment and initiate new trans-neuronal contacts. While much is known about the molecules that control filopodia extension and subsequent maturation into functional synapses, the mechanisms that regulate initiation of these dynamic, actin-rich structures have remained elusive. Here, we find that filopodia initiation is suppressed by recruitment of ArhGAP44 to actin-patches that seed filopodia. Recruitment is mediated by binding of a membrane curvature-sensing ArhGAP44 N-BAR domain to plasma membrane sections that were deformed inward by acto-myosin mediated contractile forces. A GAP domain in ArhGAP44 triggers local Rac-GTP hydrolysis, thus reducing actin polymerization required for filopodia formation. Additionally, ArhGAP44 expression increases during neuronal development, concurrent with a decrease in the rate of filopodia formation. Together, our data reveals a local auto-regulatory mechanism that limits initiation of filopodia via protein recruitment to nanoscale membrane deformations.
Highlights
During the development of the central nervous system, neuronal progenitor cells proliferate, migrate, and differentiate into functional units to form a multi-cellular neuronal network (Ayala et al, 2007)
ArhGAP44 is predominantly expressed in the brain and increases with age Formation of filopodia depends on proteins that regulate polymerization of actin filaments (Krugmann et al, 2001; Lebrand et al, 2004)
Our study shows that recruitment of ArhGAP44 to actin patches, which seed exploratory filopodia along dendritic branches, is mediated by Myosin II-dependent contraction of membrane-associated actin cables
Summary
During the development of the central nervous system, neuronal progenitor cells proliferate, migrate, and differentiate into functional units to form a multi-cellular neuronal network (Ayala et al, 2007). The formation of synaptic connections is often facilitated by dynamic exploratory filopodia that extend out of thicker dendritic branches to sample the environment and thereby increase the probability that selective preto-postsynaptic connections are established (Ziv and Smith, 1996; Marrs et al, 2001). Exploratory filopodia are dynamic finger-like membrane structures containing actin cables formed out of actin patches along the dendritic shaft (Lau et al, 1999; Matus, 2000). The frequency of filopodia formation dramatically drops once high synapse density is established (Ziv and Smith, 1996), suggesting that the initiation of these structures is controlled by opposing negative regulators.
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