PLCβ1 By-Passes Early Growth Response -1 to Induce and Maintain the Differentiation of Neuronal Cells

Abstract

Abstract The Gαq/phospholipase C-β (PLCβ) signaling system mediates calcium responses to variety of hormones and neurotransmitters. Recent studies suggest that PLCβ1 expression plays a role in the differentiation of two types of cultured neuronal cells (PC12 and SKNSH) through a mechanism independent of Gαq. Here, we show a similar increase in PLCβ1 expression when human NT2 cells are induced to differentiate either through AraC or retinoic acid. Preventing this increase abolishes differentiation. Surprisingly, transfecting PLCβ1 into undifferentiated PC12 or NT2 cells induces differentiation without the need for differentiating agents. Studies to uncover the underlying mechanism focused on the transcription factor early growth response 1 (Egr-1) which mediates the expression of many proteins involved in differentiation including PLCb1. We find that increased levels of cytosolic PLCβ1 in undifferentiated PC12 and NT2 cells promote localization of Egr-1 to the nucleus. This shift to the nucleus is correlated disruption between Egr-1 and its cytosolic binding partner (Tar RNA binding protein) when PLCβ1 is over-expressed. These studies present a novel mechanism through which PLCβ1 can modulate differentiation.