Conserved atypical cadherin, Fat2, regulates axon terminal organization in the developing Drosophila olfactory sensory neurons

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2025-02-07

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2023

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Abstract

In both insects and mammals, odor detection depends heavily on diverse classes of olfactory neurons that organize their axons to converge in a class-specific manner within the central brain’s olfactory bulb, or antennal lobe in flies. The olfactory sensory circuit is characterized by its unique and essential feature—a functionally organized topographic map. This map relies on the convergence of axons from dispersed olfactory sensory neurons of the same type into specific regions known as class-specific glomeruli. Exploring how the identity of neurons shapes this circuit organization is a central pursuit in neurobiology, given its significant implications for neurodegenerative diseases and neuronal dysfunction.In the olfactory system, various cell surface proteins, such as Robo/Slit and Toll receptors, govern numerous aspects of circuit organization, including axon guidance and synaptic matching. In our study, we have identified an atypical cadherin protein called Fat2 (also known as Kugelei) as a regulator of axon organization specific to neuronal classes. Fat2 is expressed in olfactory receptor neurons (ORNs) and local interneurons (LNs) within olfactory circuits, with minimal expression in projection neurons (PNs). Notably, Fat2 expression levels vary depending on neuronal class and peak during pupal development. In cases of fat2 gene mutations, we observed varying degrees of phenotypic presentations in ORN axon terminals belonging to different classes, with a notable trend toward more severe effects in classes with higher Fat2 expression. In the most extreme cases, fat2 mutations resulted in ORN degeneration. Our findings suggest that the intracellular domain of Fat2 is crucial for its role in organizing ORN axons. Specifically, during early stages of olfactory circuit development, Fat2 plays a pivotal role in coordinating axons precisely, facilitating the formation of class-specific glomerular structures. Importantly, our research indicates that the expression of fat2 by PNs and LNs does not significantly contribute to ORN organization. Finally, we have identified potential interactors of the Fat2 intracellular domain, namely APC family proteins (Adenomatous polyposis coli) and dop (Drop out), which likely coordinate cytoskeletal remodeling essential for axon retraction during protoglomerular development. In summary, our study establishes a foundational understanding of Fat2's role in organizing the olfactory circuit and underscores the critical importance of axon behavior in the maturation of glomeruli.

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Vien, Khanh My (2023). Conserved atypical cadherin, Fat2, regulates axon terminal organization in the developing Drosophila olfactory sensory neurons. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/30334.

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