Abstract
Through the process of neuronal differentiation, newly born neurons change from simple, spherical cells to complex, sprawling cells with many highly branched processes. One of the first stages in this process is neurite initiation, wherein cytoskeletal modifications facilitate membrane protrusion and extension from the cell body. Hundreds of actin modulators and microtubule-binding proteins are known to be involved in this process, but relatively little is known about how upstream regulators bring these complex networks together at discrete locations to produce neurites. Here, we show that Myristoylated alanine-rich C kinase substrate (MARCKS) participates in this process. Marcks−/− cortical neurons extend fewer neurites and have less complex neurite arborization patterns. We use an in vitro proteomics screen to identify MARCKS interactors in developing neurites and characterize an interaction between MARCKS and a CDC42-centered network. While the presence of MARCKS does not affect whole brain levels of activated or total CDC42, we propose that MARCKS is uniquely positioned to regulate CDC42 localization and interactions within specialized cellular compartments, such as nascent neurites.
Highlights
An essential step in nervous system development is the differentiation of neurons
We asked whether Myristoylated alanine-rich C kinase substrate (MARCKS), which is emerging as a master regulator of polarized signaling networks at the cell membrane, could have roles in neurite initiation
MARCKS is essential for Cell division cycle 42 (CDC42) apical membrane localization in radial glia[7], CDC42 and RAC1 activation in human coronary artery smooth muscle cells[10] and the distal-neurite targeting of other small GTPases in cortical neurons[11], suggesting that MARCKS could be an important regulator of signaling networks regulating neuritogenesis
Summary
An essential step in nervous system development is the differentiation of neurons Neurons begin their lives as relatively spherical cells and in the hours, days and weeks after they are born, cellular machinery is reorganized to facilitate a highly complex, sprawling morphology, often with many elaborate processes. MARCKS is essential for CDC42 apical membrane localization in radial glia[7], CDC42 and RAC1 activation in human coronary artery smooth muscle cells[10] and the distal-neurite targeting of other small GTPases in cortical neurons[11], suggesting that MARCKS could be an important regulator of signaling networks regulating neuritogenesis. This work introduces new functional roles for MARCKS in developing neurons, as well as new interactions which may prove critical for MARCKS-dependent neuritogenesis
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