Abstract

Extension of neurites from a cell body is essential to form a functional nervous system; however, the mechanisms underlying neuritogenesis are poorly understood. Ena/VASP proteins regulate actin dynamics and modulate elaboration of cellular protrusions. We recently reported that cortical axon-tract formation is lost in Ena/VASP-null mice and Ena/VASP-null cortical neurons lack filopodia and fail to elaborate neurites. Here, we report that neuritogenesis in Ena/VASP-null neurons can be rescued by restoring filopodia formation through ectopic expression of the actin nucleating protein mDia2. Conversely, wild-type neurons in which filopodia formation is blocked fail to elaborate neurites. We also report that laminin, which promotes the formation of filopodia-like actin-rich protrusions, rescues neuritogenesis in Ena/VASP-deficient neurons. Therefore, filopodia formation is a key prerequisite for neuritogenesis in cortical neurons. Neurite initiation also requires microtubule extension into filopodia, suggesting that interactions between actin-filament bundles and dynamic microtubules within filopodia are crucial for neuritogenesis.

1. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2. Department of Radiology, Division of Nuclear Magnetic Resonance Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3. Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
4. Current address: Department of Anatomy, University of Wisconsin, Madison, WI 53706, USA.
5. Current address: Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.

Correspondence to: Frank B. Gertler¹ e-mail: fgertler@mit.edu

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