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Prox1 inhibits neurite outgrowth during central nervous system development

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Abstract

During central nervous system (CNS) development, proper and timely induction of neurite elongation is critical for generating functional, mature neurons, and neuronal networks. Despite the wealth of information on the action of extracellular cues, little is known about the intrinsic gene regulatory factors that control this developmental decision. Here, we report the identification of Prox1, a homeobox transcription factor, as a key player in inhibiting neurite elongation. Although Prox1 promotes acquisition of early neuronal identity and is expressed in nascent post-mitotic neurons, it is heavily down-regulated in the majority of terminally differentiated neurons, indicating a regulatory role in delaying neurite outgrowth in newly formed neurons. Consistently, we show that Prox1 is sufficient to inhibit neurite extension in mouse and human neuroblastoma cell lines. More importantly, Prox1 overexpression suppresses neurite elongation in primary neuronal cultures as well as in the developing mouse brain, while Prox1 knock-down promotes neurite outgrowth. Mechanistically, RNA-Seq analysis reveals that Prox1 affects critical pathways for neuronal maturation and neurite extension. Interestingly, Prox1 strongly inhibits many components of Ca2+ signaling pathway, an important mediator of neurite extension and neuronal maturation. In accordance, Prox1 represses Ca2+ entry upon KCl-mediated depolarization and reduces CREB phosphorylation. These observations suggest that Prox1 acts as a potent suppressor of neurite outgrowth by inhibiting Ca2+ signaling pathway. This action may provide the appropriate time window for nascent neurons to find the correct position in the CNS prior to initiation of neurites and axon elongation.

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Acknowledgements

This research work was supported by Fondation Sante grant and the Hellenic Foundation for Research and Innovation (H.F.R.I) under the “First Call for H.F.R.I Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 1782) to P.K.P.  as well as a European Research Council grant to M.F., Agreement-309612 (TransArrest). Elpinickie Ninou was supported by the Act “Scholarships grant program for the second round of postgraduate studies” from resources of OP “Human Resources Development, Education and Lifelong Learning” 2014–2020, co-funded by the European Social Fund (ESF) and the Greek State. We would also like to thank Vagelis Harokopos (BSRC Fleming) for performing RNA-seq library preparation and sequencing, Martin Reczko (BSRC Fleming) for bioinformatic analyses, and Pavlos Alexakos, Anna Agapaki, Katerina Melachroinou, Aristidis Charonis, Antonis Stamatakis, and Panagiota Papazafiri for reagents, helpful advice, and discussions. We would also thank Dr Stamatis Pagakis, Dr Anastasios Delis, and Dr Dimosthene Mitrossilis from the Biological Imaging Unit, BRFAA, for their help on image analysis; Dr. Mitrossilis was supported by “A Greek Research Infrastructure for Visualizing and Monitoring Fundamental Biological Processes (BIO-IMAGING-GR)” (MIS 5002755) which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund).

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  1. Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27, Athens, Greece

    Valeria Kaltezioti, Iosifina P. Foskolou, Elpinickie Ninou, Matina Tsampoula & Panagiotis K. Politis

  2. Institute for Fundamental Biomedical Research, BSRC ‘Alexander Fleming’, 34 Fleming Street, Vari, 16672, Athens, Greece

    Matthieu D. Lavigne & Maria Fousteri

  3. Laboratory of Human and Animal Physiology, Department of Biology, School of Natural Sciences, University of Patras, 26500, Rio Achaias, Greece

    Marigoula Margarity

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Kaltezioti, V., Foskolou, I.P., Lavigne, M.D. et al. Prox1 inhibits neurite outgrowth during central nervous system development. Cell. Mol. Life Sci. 78, 3443–3465 (2021). https://doi.org/10.1007/s00018-020-03709-2

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