Role of cytoplasmic c-Fos as an activator of lipid synthesis during neuronal differentiation

CARDOZO-GIZZI, ANDRÉS MAURICIO; CAPUTTO, BEATRIZ LEONOR; FERRERO, GABRIEL ORLANDO; QUIROGA, SANTIAGO; RODRÍGUEZ, LUCIA; BUSTOS-PLONKA, FLORENTYNA

Córdoba

Congreso; XXXIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

Sociedad Argentina de Investigación en Neurociencias

Cytoplasmic c-Fos activates phospholipid synthesis by associating with particular lipid synthesizing enzymes at the endoplasmic reticulum (ER). This activity of c-Fos supports the high rates of membrane genesis required for neuronal differentiation. In hippocampal cultures, blocking either c-Fos expression or its activity promotes an impairment in differentiation with no observable development of axonal processes. In addition, the expression of N-terminal deletion mutants of c-Fos capable of blocking only its cytoplasmic activity produces a similar effect. Moreover, using an in utero model to evaluate neuronal cortical migration, neurons electroporated with a shRNA targeting c-Fos fail to migrate and are mostly visualized in the ventricular/subventricular zones. Since we found c-Fos strongly co-localizing with ER markers in neuronal processes, we examined if its lipid synthesis activator capacity is exerted in neurons by examining CDP-diacylglycerol synthase (CDS), previously described as one of the enzymes activated by c-Fos, and CTP:phosphocholine cytidylyltransferase-β2 (CCTβ2), that is responsible for CDP-choline formation in the brain. A strong interaction between c-Fos and the enzymes was found by FRET experiments together with a marked increase in CDS enzymatic activity in the presence of recombinant c-Fos. These results support our hypothesis that c-Fos plays a main role in neuronal differentiation and this might be achieved through phospholipid synthesis regulation.