Ferretti, Gabriella (2024) The increase in Semaphorin 3A levels during neuronal differentiation, influences axonal elongation and dendritic architecture in human neural progenitors. [Tesi di dottorato]

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Abstract

Semaphorin 3A (SEMA 3A) is a repellent guidance cue considered instrumental in many processes that shape the nervous system during development. It is produced as secreted protein in mammals, exerting both autocrine and paracrine functions. Interestingly, emerging evidence highlights the association of genetic and functional alterations of SEMA 3A or its receptors (NRP 1, PLXN A2) with neurodevelopmental disorders. Indeed, increased SEMA 3A expression levels have been detected in brains of patients with schizophrenia and several mutations in SEMA 3A, NRP 1 or PLXN A2 genes have been described in patients with autism and intellectual disabilities. Considering this, we investigated how human neural progenitors (NP) grow and differentiate after SEMA 3A overexpression. To this aim we overexpressed SEMA 3A both endogenously or exogenously using two different experimental paradigms consisting either in NP transfection with SEMA 3A DNA, or NP exposure to media from microglia overexpressing SEMA 3A. Our results indicate that increased levels of SEMA 3A affect NP morphology causing axonal retraction and aberrant arborization of apical dendrites. Additionally, SEMA 3A overexpression activate neuroinflammatory processes likely affecting NP survival. Finally, SEMA 3A seems to exert its action via Fyn-Cdk5 pathway. All these events, such as axonal retraction, disorganized dendritic arborization and neuronal death, are prevented by SEMA-3A receptors (NRP 1 or PLXN A2) silencing.

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