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Abstract

Neurogenesis is the process of generating neurons that can functionally integrate into existing neuronal circuits. In adult mammals, neurogenesis persists in specific niches such as the subventricular zone (SVZ) and the dentate gyrus (DG) which are populated by neural stem/precursor cells that produce neurons during homeostasis and injury. Processes such as alternative polyadenylation seem to play a role in NSC lineage transitions. This study also reports evidence of APA changes along the NSC lineage. Using an in vitro NSC lineage model, I was able to show the impact of APA upon translation. Additionally, I identified APLP1 as a potential APA regulator via the APLP1/CPEB4 axis. I observed the dysregulation of APA upon APLP1 knockout. Further, I was able to identify alterations in the composition of cells within the NSC lineage as a consequence of the APLP1 knockout. Dysregulation of neurogenesis can result in many different neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). ASD is characterized by deficits in social communication and the prevalence of restricted and repetitive behaviours. I showed that APLP1 knockout mice presented an ASD-like phenotype and hypothesized that APLP1/CPEB4 mediated APA may be responsible for such a phenotype by dysregulating neurogenesis. Further, owing to the 3’UTR lengthening trend observed in ASD brains, I explored the use of an APA phenotype for ASD diagnosis. The current diagnosis of ASD relies primarily on clinical symptoms that assess behavioural deficits and to some extent morphological abnormalities associated with NDDs. Early diagnosis is essential to allow for necessary intervention at the right time. Molecular diagnosis of ASD is limited to large genetic screens that can identify individual mutations that link to syndromic ASD but fail to diagnose idiopathic ASD. Therefore, I investigated the changes in the APA landscape between ASD patients and controls using whole blood and found great potential in such an application.