ARMS/Kidins220 temporally coordinates neurotrophin-mediated differentiation and -regulated BDNF secretion

Resumen del trabajo presentado al XXXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Valencia del 7 al 10 de septiembre de 2015.
During nervous system development secretion must be tightly controlled meanwhile neurons differentiate projecting axons and dendrites to their specific targets. Neurotrophins regulate, among other functions, differentiation and regulated secretion in the nervous system. However, the molecular mechanisms underlying the temporal coordination of differentiation and secretion by neurotrophins are unknown. Here we describe the involvement of ARMS/Kidins220, a downstream protein of Trk neurotrophin receptors, acting through Synembryn-B and Trio in the regulated secretion mediated by neurotrophins. We observed that PC12 differentiation and regulated secretion are temporally controlled since non-differentiated or differentiated neurons display a poor or strong regulated secretion in response to neurotrophins, respectively. Interestingly, high levels of ARMS/Kidins220 and Synembryn-B are required for differentiation, when regulated secretion is minimal, whereas a strong downregulation of both proteins occurred once the cells are differentiated, when regulated secretion is maximal. Overexpression or downregulation of ARMS/Kidins220 and Synembryn-B levels in non-differentiated PC12 cells blocks or potentiates NGF-mediated secretion, respectively. Similarly, secretion of BDNF in cortical neurons in response to NT-3 or NT-4 augments with a concomitant downregulation of ARMS/Kidins220 and Synembryn-B protein levels. In addition, knockdown of ARMS/Kidins220 and Synembryn-B potentiated further BDNF evoked secretion. Finally, downregulation of ARMS/Kidins220 protein in vivo enhanced BDNF secretion from cortex in response to depolarization, NT-3 or NT-4 and a signifi cant accumulation of BDNF in the striatum coming from the cortex and hippocampus.