Intercellular interactions between neurons and glia impact diverse neurological diseases, from autism and schizophrenia to amyotrophic lateral sclerosis (ALS) and Alzheimer's disease, as well as responses to stroke and traumatic brain injury. Some of the most important interactions occur at synapses, where the dendritic spines that receive information are attached to astrocytic glia. The molecular mechanisms that assemble these cell-cell attachments remain elusive, owing to the challenges associated with the complexity of the mammalian brain. The goal of this study is to overcome these challenges using an innovative model of dendrite- glia interaction in C. elegans. As described below, the central hypothesis is that dendrite-glia contacts are mediated by proteins from adherens junctions (AJs) in epithelia. Thus, this study lies at the intersection of two fields: applying knowledge of AJs from epithelial biology to a long-standing question in glial biology and, conversely, leveraging the diversity of glial biology to investigate how AJ proteins can be deployed in cellular contexts outside epithelia. In preliminary data, innovative approaches enabled analysis of a novel class of dendrite-glia contact. Two neurons, URX and BAG, extend dendrites to the nose where they intimately wrap a single defined glial cell, the lateral ILso glia. Genetic screens identified factors (SAX-7, GRDN- 1, MAGI-1) that act in glia to anchor these dendrites at the nose during embryonic elongation. When these factors are disrupted, developing dendrites detach from the nose and fail to fully extend. SAX-7/L1CAM is a conserved neuron-glia adhesion molecule, GRDN-1 is a conserved cytoskeletal adaptor, and MAGI-1 is a conserved scaffolding protein. Each of these proteins is associated with AJs in epithelia; glial-specific depletion of the core AJ protein cadherin (HMR-1) also causes the same defects, leading to the idea that AJs mediate dendrite-glia attachments.
The Aims of this study are to (Aim 1) determine the role of AJs in dendrite-glia interaction using localization and cell-specific depletion experiments;
(Aim 2) define the molecular roles of SAX- 7, GRDN-1, and MAGI-1 using in vivo rescue and in vitro binding assays;
and (Aim 3) identify additional players in this novel junction using genetic screens, focusing initially on a MAP kinase and a formin-related protein as new players. The longer-term goal is to study these proteins in a mouse glia model, thus translating genetic discoveries from C. elegans to mammalian brain.
Interactions between neurons and glia in the human brain have been implicated in disorders ranging from schizophrenia to Alzheimer's disease, as well as in how the brain responds to stroke or traumatic brain injury. Yet, the complexity of the brain has made it difficult to identify the molecular players that mediate cell-cell attachments responsible for neuron-glia interactions. This proposal will use a simple but powerful genetic system, the nematode worm C. elegans, to identify the cell attachment molecules that control neuron-glia interactions, thus opening the door to future work that will determine how these pathways are altered in human disease.
