Erik Dent

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The goal of our research is to understand the mechanisms of central nervous system development and plasticity at the cellular and molecular level.  Nervous system structure and function is especially dependent on the cytoskeleton, which is comprised of three polymer systems: actin filaments, microtubules (MTs) and neurofilaments/intermediate filaments. We study both early and late events in the lifecycle of neurons, including neuronal migration, neurite outgrowth, and synaptic plasticity in dendritic spines. Within these general areas of development and plasticity the lab is focused on how F-BAR proteins function with the actin cytoskeleton in neuronal development and how MT dynamics play important roles in synaptic plasticity in mature dendrites. We use molecular and biochemical approaches, with a focus on high-resolution live cell microscopy.

F-BAR proteins in neuronal development
F-BAR proteins are intracellular membrane binding proteins that detect and sculpt plasma membrane curvature. They are named after their F-BAR region which forms a crescent-shaped dimer that binds to acidic membrane lipids. We study the CIP4 subfamily of F-BAR proteins, composed of CIP4, FBP17 and TOCA1. These proteins, in addition to the F-BAR domain, contain an HR1 domain that binds active GTPases, including Cdc42 and Rac1, and an SH3 domain that binds actin-associated proteins and dynamin. In most cell types this family of proteins is involved in tubulating endocytosing membrane. However, we discovered that one family member, CIP4, appears to function in membrane protrusion in neurons. We are studying how this family of proteins tightly regulate neurite formation, an exceptionally important process in early neuronal development that affects neuronal migration and axon/dendrite outgrowth. These proteins are also affected in several forms of cancer, underscoring their importance in health and disease.

Microtubule polymerization into dendritic spines
Several years ago, we discovered that microtubules (MTs) remain dynamic, polymerizing and depolymerizing, throughout the life of a post-mitotic neuron and can explore the entire intracellular environment of the neuron. Moreover, we showed that MTs polymerize directly into dendritic spines in an activity-dependent fashion and can transport specific vesicular cargo into spines. These MT “invasions” are transient, only lasting seconds to minutes, and are infrequent. However, they specifically target spines that are undergoing synaptic plasticity. Consistently, MT invasions are dependent on NMDA receptor activation, calcium influx and actin polymerization in spines. To determine the function of these MT invasions of dendritic spines we are developing methodologies to specifically disrupt entry of MTs into dendritic spines, while leaving their dynamics intact in other regions of the neuron. Importantly, disruption of MT dynamics is likely to give rise to both neurodevelopmental and neurodegenerative diseases.

See publications here.