Project Summary/Abstract Molecular basis and function of alternative nuclear architectures in mouse neurons Every eukaryotic cell must fold its genome within its nucleus. Microscopy and genomic methods have revealed regular features of how the genome is packaged and organized that are widely shared by mammalian cells. Our lab seeks to understand cases where cells bend these rules to instead form unusual structures that achieve a cell-type specific purpose. Our prior work in mouse olfactory sensory neurons exemplifies such a case. Olfactory sensory neurons reorganize the DNA in their nucleus to that genes that are off are located in the middle of the nucleus instead of at the periphery. At the same time, these cells bring together olfactory receptor genes from different chromosomes in 3D space to form specialized gene hubs. These hubs are unique to olfactory sensory neurons and govern a critical gene regulatory mechanism that defines the identity of these neurons and is central to our sense of smell. We seek to determine whether such alternative nuclear architectures are rare outliers or whether they are more widespread than currently known. We hypothesize that alternative architectures may be particularly common in the nervous system, where long-lived post-mitotic neurons have a long time to rearrange their DNA, and that they may be critical to understanding how neurons change in response to stimuli. We will develop new ways of identifying alternative nuclear architectures that will allow us to identify when and where they form, and we will use primary mouse neurons from the olfactory system and the spinal cord to explore the function and regulation of these fascinating structures.