Involvement of the mouse Prp19 gene in neuronal/astroglial cell fate decisions

Abstract

The molecular mechanisms involved in neuronal/astroglial cell fate decisions during the development of the mammalian central nervous system are poorly understood. Here, we report that PRP19β, a splice variant of mouse PRP19α corresponding to the yeast PRP19 protein, can function as a neuron-astroglial switch during the retinoic acid-primed neural differentiation of P19 cells. The β-variant possesses an additional 19 amino acid residues inframe in the N-terminal region of the β-variant. The forced expression of the β-variant RNA caused the down-regulation of oct-3/4 and nanog mRNA expression during the 12-48 h of the late-early stages of neural differentiation and was sufficient to convert P19 cells into neurons (but not glial cells) when the cells were cultured in aggregated form without retinoic acid. In contrast, the forced expression of the β-variant RNA suppressed neuronal differentiation and conversely stimulated astroglial cell differentiation in retinoic acid-primed P19 cells. Based on yeast two-hybrid screening, cyclophilin A was identified as a specific binding partner of the β-variant. Luciferase reporter assay mediated by the oct-3/4 promoter revealed that cyclophilinAcould act as a transcriptional activator and that its activity was suppressed by the β-variant, suggesting that cyclophilin A takes part in the induction of oct-3/4 gene expression, which might lead to neuroectodermal otx2 expression within 12 h of the immediate-early stages of retinoic acid-primed neural differentiation. These results show that the β-variant gene plays a pivotal role in neural differentiation and that the β-variant participates in neuronal/astroglial cell fate decisions. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.