Abstract
ABSTRACTGenetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology.
Highlights
The cadherin superfamily of cell adhesion molecules consists of more than one hundred members that are subdivided into distinct subfamilies, including classical type I and type II cadherins, clustered and non-clustered protocadherins, and atypical FAT cadherins (Hulpiau and van Roy, 2009; Hirano and Takeichi, 2012)
We investigated the association of FAT1 with autism spectrum disorder (ASD) by analyzing its expression in neural precursor cells (NPCs) differentiated from induced pluripotent stem cells derived from individuals with autism compared to those from control individuals
Our findings suggest a potential function of FAT1 in the cerebellum during early postnatal development and strengthen its association with ASD by showing altered expression levels of FAT1 in autism-specific NPCs
Summary
The cadherin superfamily of cell adhesion molecules consists of more than one hundred members that are subdivided into distinct subfamilies, including classical type I and type II cadherins, clustered and non-clustered protocadherins, and atypical FAT cadherins (Hulpiau and van Roy, 2009; Hirano and Takeichi, 2012). We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer.
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