Functional interdependence of the actin nucleator Cobl and Cobl-like in dendritic arbor development

Abstract

Local actin filament formation is indispensable for development of the dendritic arbor of neurons. We show that, surprisingly, the action of single actin filament-promoting factors was insufficient for powering dendritogenesis. Instead, this process required the actin nucleator Cobl and its only evolutionary distant ancestor Cobl-like acting interdependently. This coordination between Cobl-like and Cobl was achieved by physical linkage by syndapin I. Syndapin I formed nanodomains at convex plasma membrane areas at the base of protrusive structures and interacted with three motifs in Cobl-like, one of which was Ca2+/calmodulin-regulated. Consistently, syndapin I, Cobl-like’s newly identified N terminal calmodulin-binding site and the single Ca2+/calmodulin-responsive syndapin-binding motif all were critical for Cobl-like’s functions. In dendritic arbor development, local Ca2+/CaM-controlled actin dynamics thus relies on regulated and physically coordinated interactions of different F-actin formation-promoting factors and only together they have the power to bring about the sophisticated neuronal morphologies required for neuronal network formation.

Post-stroke dendritic arbor regrowth – a cortical repair process requiring the actin nucleator Cobl

“…Indeed, Cobl functions require arginine methylation of one of its three G-actin binding WH2 domains by the arginine methyltransferase PRMT2 (Hou et al, 2018). Furthermore, Cobl's N terminal membrane-associating domain (the Cobl Homology domain) interacts with syndapin I in a Ca 2+ /CaM-regulated manner in early neuromorphogenesis (Hou et al, 2015) and links Cobl to its functional partner Cobl-like (Izadi et al, 2021). Strikingly, also Cobl's actin nucleating, WH2 domain-containing C terminal part was found to be controlled by association of Ca 2+activated CaM (Hou et al, 2015).…”

“…The defects caused by MCAO in pyramidal neurons in cortical layers II/III and V of the murine primary motor cortex seemed somewhat related to those observed for Cobl loss-of-function in immature rat hippocampal neurons in culture (Ahuja et al, 2007;Izadi et al, 2021). We therefore addressed whether Cobl may also play some important role in shaping cortical neurons and whether furthermore Cobl may not do so not only in developing neurons in culture but also in adult neurons in the cortex of mice with a demand for remapping neuronal circuits subsequent to stroke.…”

“…The morphology of the complex dendritic arbor of neuronal cells is stabilized by microtubules, yet, it is the de novo generation of actin filaments that powers the formation of initial protrusions from dendrites that establishes the dendritic arbor (Kessels et al, 2011). The Wiskott-Aldrich domain 2-based actin nucleator Cobl (Ahuja et al, 2007;Qualmann and Kessels, 2009) (gi:32251014) is widely expressed in the brain (Haag et al, 2012) and was demonstrated to be critical for dendritic branching of developing hippocampal neurons (Ahuja et al, 2007) and of Purkinje cells (Haag et al, 2012) together with assessory machinery (Haag et al, 2012;Schwintzer et al, 2011;Izadi et al, 2021). Interestingly, the functions of the actin nucleator Cobl hereby show regulations by arginine methylation by PRMT2 (Hou et al, 2018) and by multiple Ca 2+ /calmodulin (CaM)-mediated mechanisms directly converging onto Cobl (Hou et al, 2015).…”