Prox1 inhibits neurite outgrowth during central nervous system development
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Prox1 inhibits neurite outgrowth during central nervous system development Valeria Kaltezioti1 · Iosifina P. Foskolou1 · Matthieu D. Lavigne2 · Elpinickie Ninou1 · Matina Tsampoula1 · Maria Fousteri2 · Marigoula Margarity3 · Panagiotis K. Politis1 Received: 24 January 2020 / Revised: 6 November 2020 / Accepted: 11 November 2020 © Springer Nature Switzerland AG 2020
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 C a2+ signaling pathway, an important mediator of neurite extension and neuronal maturation. In accordance, Prox1 represses C a2+ 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. Keywords Axon extension · Calcium signaling · CamkII · CREB phosphorylation · Neuronal maturation
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03709-2) contains supplementary material, which is available to authorized users. * Panagiotis K. Politis [email protected] 1
Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27 Athens, Greece
2
Institute for Fundamental Biomedical Research, BSRC ‘Alexander Fleming’, 34 Fleming Street, Vari, 16672 Athens, Greece
3
Laboratory of Human and Animal Physiology, Department of Biology, School of Natural Sciences, University of Patras, 26500 Rio Achaias, Greece
One of the most challenging endeavors of biomedical research is to unravel the molecular mechanisms that regulate div
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