The neocortex contains a great diversity of neuronal subtypes that wire precisely into local and long- distance circuits to execute higher-order functions. To understand the cell-autonomous mechanisms that govern the generation and maintenance of individual classes of neurons, defined neuronal populations have been purified and molecularly profiled across development. However, much less is known about how neurons, once generated, maintain their class-specific traits over long periods of time. Cell intrinsic mechanisms, including transcriptional and epigenetic changes, are being actively studied, yet little is known regarding the role of the extracellular environment. Specifically, the extracellular matrix (ECM) contains many molecules that regulate neuronal function, from migration to synaptogenesis, and its degradation enables synaptic plasticity, wiring, and axonal regeneration, yet little is known about how it influences and is influenced by neuronal identity. Broadly, the goal of this proposal is to understand the contribution of extracellular matrix molecules to the maintenance of neuronal identity. Specifically, I ask: 1. Do different classes of projection neurons produce distinct ECM molecules that help define the molecular composition of their local extracellular microenvironment? 2. Does reprogramming one class of projection neuron into another in vivo result in a change in ECM composition? 3. Does the ECM maintain projection neuron identity through the lifespan of the organism? Here, I propose a set of feasible experiments to explore these questions that builds upon my preliminary data and takes advantage of the expertise of the Arlotta lab. Indeed, my preliminary data already suggests that different subclasses of neurons differentially express ECM-related genes. Answering these questions will reveal a new role for cell-extrinsic cues on neuronal development, highlight an unexplored form of neural plasticity, and pave the way for reprogramming neuronal subtypes in the adult brain, and repairing tissue and circuits upon CNS injury.
Neuronal loss from neurological disorders and mental illnesses are often irreversible, and treatments for these debilitating diseases are currently limited. Here, we propose to explore for the very first time the contribution of the extracellular matrix to the maintenance of neuronal identity, in hope of illuminating strategies to regenerate specific classes of neurons by reprogramming neighboring neurons of a different identity.
