Conserved atypical cadherin, Fat2, regulates axon terminal organization in the developingDrosophilaolfactory sensory neurons

Abstract A unique and defining characteristic of the olfactory sensory circuit is its functionally organized topographic map, which requires widely dispersed olfactory sensory neurons with the same identity to converge their axons into one neuropil, a class-specific glomerulus. Understanding the process of how neuronal identity confers circuit organization is a major endeavor in the field of neurobiology due to its intricate connection to neurodegeneration and neuronal dysfunction. In the olfactory system, many aspects of circuit organization, from axon guidance to synaptic matching, are regulated by a variety of cell surface proteins (for example Robo/Slit and Toll receptors). In this paper, we’ve identified a novel atypical cadherin protein, Fat2 (also known as Kugelei), as a regulator of class-specific axon organization. Fat2 is expressed in olfactory receptor neurons (ORNs) and local interneurons (LNs) within the olfactory circuits, but little to no expression is found in projection neurons (PNs). Fat2 expression levels vary in a neuronal class-specific manner and peak during pupal development. In fat2 null mutants, ORN axon terminals belonging to different ORN classes present with varying phenotypic severity with the highest fat2 expressing classes being most severely affected. In the most extreme cases, fat2 mutations lead to ORN degeneration. We then show evidence that suggests Fat2 intracellular domain is necessary for Fat2 function in ORN axon organization. Within the developmental context, Fat2 is required starting at early stages of olfactory circuit development specifically for precise axon retraction to further condense class-specific glomeruli. We’ve also shown that PNs’ and LNs’ expression of Fat2 likely does not contribute to ORN organization 1 . Lastly, we narrow down potential Fat2 intracellular domain interactors, APC family proteins (Adenomatous polyposis coli) and dop (Drop out), that likely orchestrate the cytoskeletal remodeling required for axon retraction during protoglomerular development. Altogether, we provide a foundational understanding of how Fat2 functions in olfactory circuit organization and implicate the critical role of axon retraction during glomerular maturation.