Characterization of midbody remnant mediated cell fate decisions in autism

ABSTRACT Asymmetric division of neural progenitor cells (NPCs) is critical for the formation of the diverse cell types and complex architecture of the cerebral cortex. Abnormalities in this process have been consistently observed in autism spectrum disorder (ASD), manifesting as altered NPC proliferation, dysregulation of cellular signaling pathways, and structural changes within the cortex. These recurrent findings across ASD subtypes hint at asymmetric NPC division as a potential mechanistic nexus in ASD pathogenesis. Yet, the common pathways through which various ASD risk factors impact this process remain largely unexplored, obscuring the developmental origins of ASD. Our collective aim, leveraging the collaborative efforts of the Wolter and Skop labs, is to unearth causal molecular mechanisms driving neurodevelopmental alterations in ASD. Our recently published preliminary data introduces a novel form of intercellular communication implicated in ASD: the transfer of genetic material via midbody remnants (MBRs). Contrary to past beliefs, these large extracellular vesicles are now recognized for their role in cell fate determination, facilitated by the transfer of cell-type- specific mRNAs. Our data suggests an accumulation of MBRs laden with ASD risk gene mRNAs in the proliferative zones of the developing human cortex, suggesting that MBR dynamics may influence cortical development in ASD. This proposal aims to elucidate the impact of MBR-mediated genetic information transfer on the cortical cellular composition in the context of an ASD linked mutation (PTEN(+/-)). We hypothesize that PTEN haploinsufficiency alters the molecular composition of MBRs, influencing NPC proliferation and neuronal differentiation. Aim #1 focuses on determining how an ASD-associated PTEN mutation alters MBR molecular landscape, utilizing RNA sequencing and cell surface proteomics in PTEN(+/-) iPSC lines during neural differentiation. Aim #2 examines how MBR uptake influences cell division and neurogenesis in PTEN(+/-) cortical organoids, employing mosaic organoids and a novel reporter system to trace MBR autonomous effects. By addressing the unknowns of how transfer of genetic information via MBRs affects cortical development in ASD, this research promises to pioneer a new investigative path in ASD research, setting the stage for subsequent in- depth studies on MBR's molecular mechanisms in ASD.