An increase in Semaphorin 3A biases the axonal direction and induces an aberrant dendritic arborization in an in vitro model of human neural progenitor differentiation

Abstract

Abstract Background Semaphorins (Sema) belong to a large family of repellent guidance cues instrumental in guiding axons during development. In particular, Class 3 Sema (Sema 3) is among the best characterized Sema family members and the only produced as secreted proteins in mammals, thereby exerting both autocrine and paracrine functions. Intriguingly, an increasing number of studies supports the crucial role of the Sema 3A in hippocampal and cortical neurodevelopment. This means that alterations in Sema 3A signaling might compromise hippocampal and cortical circuits and predispose to disorders such as autism and schizophrenia. Consistently, increased Sema 3A levels have been detected in brain of patients with schizophrenia and many polymorphisms in Sema 3A or in the Sema 3A receptors, Neuropilins (Npn 1 and 2) and Plexin As (Plxn As), have been associated to autism. Results Here we present data indicating that when overexpressed, Sema 3A causes human neural progenitors (NP) axonal retraction and an aberrant dendritic arborization. Similarly, Sema 3A, when overexpressed in human microglia, triggers proinflammatory processes that are highly detrimental to themselves as well as NP. Indeed, NP incubated in microglia overexpressing Sema 3A media retract axons within an hour and then start suffering and finally die. Sema 3A mediated retraction appears to be related to its binding to Npn 1 and Plxn A2 receptors, thus activating the downstream Fyn tyrosine kinase pathway that promotes the threonine-serine kinase cyclin-dependent kinase 5, CDK5, phosphorylation at the Tyr15 residue and the CDK5 processing to generate the active fragment p35. Conclusions All together this study identifies Sema 3A as a critical regulator of human NP differentiation. This may imply that an insult due to Sema 3A overexpression during the early phases of neuronal development might compromise neuronal organization and connectivity and make neurons perhaps more vulnerable to other insults across their lifespan.

Keywords

• Semaphorin 3A
• Neurodevelopment
• Neuroinflammation
• Microglia
• Neural progenitors