Protein arginine methylation by PRMT2 – a putative versatile posttranslational regulatory mechanism for controlling actin nucleation underlying proper neuromorphogenesis

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The brain encompasses a sophisticated network of neuronal cells with extremely elaborated morphologies of their signal-sending (axonal) and –receiving (dendritic) compartments. De novo actin filament formation is one of the major driving and steering forces for the development and plasticity of the neuronal arbor. Actin filament assembly thus requires tight temporal and spatial control. Such control is most effective at the level of regulating actin nucleation promoting factors, as these are key components for filament formation. Our recent results unveiled that Cobl, an actin nucleator critical for shaping the dendritic arbor of neuronal cells, is controlled by arginine methylation. This was unexpected, as arginine methylation is a posttranslational modification previously known to predominantly control nuclear processes. The protein arginine methyltransferase PRMT2 was identified to associate with Cobl and regulate its cytoskeletal properties. Importantly, we found that PRMT2 also was critical for dendritic arborization and that its crucial role required its enzymatic activity and a protein interaction domain unique for this protein arginine methyltransferase. The identification of additional highly brain-enriched actin nucleation promoting factors as further interaction partners of PRMT2 in our mass spectrometry screen now led to the exciting working hypothesis that arginine methylation may be a more general and versatile mean for controlling neuronal network formation and proper brain function. We therefore here propose to investigate whether PRMT2 is also responsible for posttranslational modification of an additional actin nucleation promoting factor implicated in neuromorphogenesis found in our mass spectrometry screen. Subsequent studies aim at unveiling the molecular mechanistic consequences of PRMT2-mediated arginine methylation of this important actin cytoskeletal component on its cytoskeletal properties and its regulatory protein network interactions. Functional studies in neurons will be conducted in order to uncover a putative generalized function of PRMT2-mediated arginine methylation in dendritic arborization mediated by actin nucleation promoting factors.Further important aspects in neuronal network formation are axonal development and the establishment of pre- and postsynaptic specializations subsequent to neurite induction and branching. Since also the induction and plasticity of these specialized morphological compartments of neurons have been demonstrated to be highly dependent on actin organization and dynamics, we propose to unveil whether and to what extent the function of PRMT2 in neuronal morphology control reaches beyond dendritic arborization.Together, this work will provide important insights into regulatory posttranslational mechanisms targeting actin nucleation-promoting factors crucial for neuromorphogenesis and thereby shed light on a key process for the formation of neuronal networks in vertebrate brains.