UNDERSTANDING THE ROLES OF ACTIN REGULATORS INVOLVED IN SYNAPSE FORMATION

Abstract

Aberrant synaptic connectivity in the brain is implicated in many neurodevelopmental and psychiatric disorders. Synaptogenesis is preceded by thin, fingerlike protrusions called dendritic filopodia (DF), whose morphology and dynamics are dependent on actin. There are three major classes of proteins that are involved in the regulation of actin in DF of neurons: the Ena/VASP protein family, formins, and Arp2/3, with EVL of the Ena/VASP protein family being the least characterized. The relationship between these three classes of proteins in actin regulation also remains unclear. Changing the expression and activity level of these proteins using knockdown, knockout, and pharmacological inhibition in cultured murine cortical neurons, we found that EVL plays a dominant role in the regulation of the morphology and dynamics of DF. We have also identified Daam1, Daam2, Fmn1, or Fmn2 as four possible formin paralogs that may cooperate with EVL to regulate DF motility. We hypothesize that formins may nucleate DF, while EVL polymerizes i t. Because many neurological disorders arise from dysfunctional DF due to the misregulation of the cytoskeleton in neurons, understanding how formins and EVL work together to regulate the actin cytoskeleton can open the door to further studies into the mec hanism and treatment of these diseases.