Role of CREB3 transcription factors in neuronal differentiation models

SAMPIERI, L; FUNES CHABÁN, MACARENA; ROZÉS-SALVADOR, VICTORIA; ALVAREZ, CECILIA

Santa Cruz

Workshop; EMBO Workshop Emerging Concepts of the Neuronal Cytoskeleton; 2023

IUBMB EMBO

Neuronal processes such as growth and differentiation demand extensive membrane remodeling andprotein redistribution. Formation of new neuritic processes required the adaptation of the secretorypathway, which is regulated, in multiple cell types, by members of the CREB3 family of transcriptionfactors. CREB3 factors have emerged as signaling hubs for the regulation of Golgi homeostasis,integrating stimuli to control cellular events that impact membrane expansion and composition.Although recent studies have focused on their role in the central nervous system, little is known aboutCREB3 factors in neuronal differentiation. Here, we analyze the expression of CREB3 family membersusing two models: i) NGF-induced PC12 cell differentiation and ii) differentiation of embryonic rathippocampal neurons. The results show that NGF treatment or developing hippocampal neuronsincreases the expression of some proteins necessary for membrane transport (transport factors). Inaddition, a significant increase in CREB3L2 mRNA and protein levels is detected in response to NGF,and expression of both CREB3L1 and CREB3L2 increase in hippocampal neurons (1-7DIV).Interestingly, CREB3L2-overexpression hampers NGF-induced neurite outgrowth, while its inhibitionenhances it. Consistent with this, CREB3L2-overexpressing PC12 cells show higher expression ofGTPase Rab5 (a negative regulator of PC12 differentiation) than control cells. In contrast, inhippocampal neurons, CREB3L1 expression is higher than CREB3L2, and overexpression of aCREB3L1 dominant negative construct reduces axonal growth and increases Golgi fragmentation,compared to controls. Taken together, our findings strongly suggest that CREB3 factors are involved inneuronal differentiation by modulating the adaptation of the secretory pathway.Financing: PICT 2019-1625, BID from the Ministry of Science and Technology of Argentina and SECyT-UNC (2018–2021) from UniversidadNacional de Córdoba