ZNF536, a Novel Zinc Finger Protein Specifically Expressed in the Brain, Negatively Regulates Neuron Differentiation by Repressing Retinoic Acid-Induced Gene Transcription

Abstract

Neuronal differentiation is tightly regulated by a variety of factors. In a search for neuron-specific genes, we identified a highly conserved novel zinc finger protein, ZNF536. We observed that ZNF536 is most abundant in the brain and, in particular, is expressed in the developing central nervous system and dorsal root ganglia and localized in the cerebral cortex, hippocampus, and hypothalamic area. During neuronal differentiation of P19 cells induced by retinoic acid (RA), ZNF536 expression is increased at an early stage, and it is maintained at a constant level in later stages. Overexpression of ZNF536 results in an inhibition of RA-induced neuronal differentiation, while depletion or mutation of the ZNF536 gene results in an enhancement of differentiation. We further demonstrated that ZNF536 inhibits expression of neuron-specific marker genes, possibly through the inhibition of RA response element-mediated transcriptional activity, as overexpression of RA receptor α can rescue the inhibitory role of ZNF536 in neuronal differentiation and neuron-specific gene expression. Our studies have identified a novel zinc finger protein that negatively regulates neuron differentiation.

ACKNOWLEDGMENTS

This work was supported by Tsinghua-Yue-Yuan Medical Sciences Fund and grants from the National Natural Science Foundation of China (30530420, 30611120522) and the Chinese National Support Project (2006CB910102).

We are grateful to Yang Shi (Harvard Medical School), Xin-Yuan Fu (Indiana University School of Medicine), and Xiaofan Wang (Duke University) for their support and suggestions on this project. We thank Takahiro Nagase (KAZUSA DNA research institute, Japan) and Merlin Crossley (The University of Sydney, Australia) for providing constructs. We thank David M. Irvin (University of Toronto) for reading the manuscript.