Abstract
The formation of dendritic arbors in neurons is a highly regulated process. Among the regulators of dendritogenesis are numerous membrane proteins that are eventually internalized via clathrin-mediated endocytosis. AP2 is an adaptor complex that is responsible for recruiting endocytic machinery to internalized cargo. Its direct involvement in dendritogenesis in mammalian neurons has not yet been tested. We found that the knockdown of AP2b1 (β2-adaptin), an AP2 subunit, reduced the number of dendrites in developing rat hippocampal neurons and decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2 levels by inhibiting mechanistic/mammalian target of rapamycin (mTOR). The dendritic tree abruption that was caused by AP2b1 knockdown was rescued by the overexpression of GluA2 or restoration of the activity of the mTOR effector p70S6 kinase (S6K1). Altogether, this work provides evidence that the AP2 adaptor complex is needed for the dendritogenesis of mammalian neurons and reveals that mTOR-dependent GluA2 biosynthesis contributes to this process.
Highlights
Classes of neurons with different functions have unique shapes of dendritic arbors to ensure the accurate responses of neurons to information they receive [1]
Clathrin-mediated endocytosis (CME) is important for mammalian dendritogenesis, the direct involvement of AP2 has not been studied to date
DIV8 hippocampal neurons were transfected with plasmids encoding AP2b1 Short-hairpin RNAs (shRNAs), and the Total number of dendritic tips (TNDT) was counted after 4 days (Fig. 1c, d)
Summary
Classes of neurons with different functions have unique shapes of dendritic arbors to ensure the accurate responses of neurons to information they receive [1]. The multistep process of dendritic tree development is tightly regulated by various extracellular and intracellular factors [2,3,4], but cross-talk between various factors during dendritogenesis has been scarcely investigated. In CME, the intake of cargo occurs via membranous clathrin-coated pit with the help of a wide range of accessory adaptor proteins, including the AP2 adaptor complex [5]. AP2 is composed of four subunits: AP2a1 (α1adaptin)/AP2a2 (α2-adaptin), AP2b1 (β2-adaptin), AP2m1 (adaptin-μ2), and AP2s1 (σ2-adaptin) These subunits bind cargo (AP2b1 and AP2m1), the plasma membrane (AP2a1/2 and AP2m1), clathrin, and other accessory proteins (e.g., Eps and AP180 [AP2b1]) [6]. CME contributes to neuronal development (e.g., dendritic growth and pruning; [10,11,12,13,14] and synaptic plasticity [9]). The particular role of AP2 during dendritogenesis has been scarcely investigated [12] and, to date, evidence is still lacking concerning the role of AP2 in mammalian dendritogenesis
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