Original Research ARTICLE
Brain-derived neurotrophic factor (BDNF) regulates Rab5-positive early endosomes in hippocampal neurons to induce dendritic branching
- 1Physiology, Pontificia Universidad Católica de Chile, Chile
Neurotrophin receptors use endosomal pathways for signaling in neurons. However, how neurotrophins regulate the endosomal system for proper signaling is unknown. Rabs are monomeric GTPases that act as molecular switches to regulate membrane trafficking by binding a wide range of effectors. Among the Rab GTPases, Rab5 is the key GTPase regulating early endosomes and is the first sorting organelle of endocytosed receptors. The objective of our work was to study the regulation of Rab5-positive endosomes by BDNF at different levels, including dynamic, activity and protein levels in hippocampal neurons. Short-term treatment with BDNF increased the colocalization of TrkB in dendrites and cell bodies, increasing the vesiculation of Rab5-positive endosomes. Consistently, BDNF increased the number and mobility of Rab5 endosomes in dendrites. Cell body fluorescence recovery after photobleaching of Rab-EGFP-expressing neurons suggested increased movement of Rab5 endosomes from dendrites to cell bodies. These results correlated with the BDNF-induced activation of Rab5 in dendrites, followed by increased activation of Rab5 in cell bodies. Long-term treatment of hippocampal neurons with BDNF increased the protein levels of Rab5 and Rab11 in an mTOR-dependent manner. While BDNF regulation of Rab5a levels occurred at both the transcriptional and translational levels, Rab11a levels were regulated at the translational level at the time points analyzed. Finally, expression of a dominant-negative mutant of Rab5 reduced the basal arborization of nontreated neurons, and although BDNF was partially able to rescue the effect of Rab5DN at the level of primary dendrites, BDNF-induced dendritic branching was largely reduced. Our findings indicate that BDNF regulates the Rab5-Rab11 endosomal system at different levels and that these processes are likely required for BDNF-induced dendritic branching.
Keywords: BDNF, hippocampal neurons, Rab5, Early endosomes, Dendrites, branching process, trafficking
Received: 07 Jun 2018;
Accepted: 30 Nov 2018.
Edited by:Enrica Maria Petrini, Fondazione Istituto Italiano di Technologia, Italy
Reviewed by:Guangpu Li, University of Oklahoma Health Sciences Center, United States
Maurizio Renna, University of Cambridge, United Kingdom
Dawen Cai, University of Michigan, United States
Copyright: © 2018 Moya-Alvarado, Gonzalez, Stuardo and Bronfman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Francisca C. Bronfman, Pontificia Universidad Católica de Chile, Physiology, Santiago, Chile, email@example.com