NPAS3 Regulates Transcription and Expression of VGF: Implications for Neurogenesis and Psychiatric Disorders.

Dongxue Yang,Arshad Padhiar,Wenbo Zhang,Yu Zhang,Yonghui Shi,Tiezheng Zheng,Min Huang,Kaspar Davis,Yuyuan Li,Yao Yue,Li Sha

doi:10.3389/fnmol.2016.00109

Abstract

Neuronal PAS domain protein 3 (NPAS3) and VGF (VGF Nerve Growth Factor (NGF) Inducible) are important for neurogenesis and psychiatric disorders. Previously, we have demonstrated that NPAS3 regulates VGF at the transcriptional level. In this study, VGF (non-acronymic) was found regulated by NPAS3 in neuronal stem cells. However, the underlying mechanism of this regulation remains unclear. The aim of this study was to explore the correlation of NPAS3 and VGF, and their roles in neural cell proliferation, in the context of psychiatric illnesses. First, we focused on the structure of NPAS3, to identify the functional domain of NPAS3. Truncated NPAS3 lacking transactivation domain was also found to activate VGF, which suggested that not only transactivation domain but other structural motifs were also involved in the regulation. Second, Mutated enhancer box (E-box) of VGF promoter showed a significant response to this basic helix-loop-helix (bHLH) transcription factor, which suggested an indirect regulatory mechanism for controlling VGF expression by NPAS3. κB site within VGF promoter was identified for VGF activation induced by NPAS3, apart from direct binding to E-box. Furthermore, ectopically expressed NPAS3 in PC12 cells produced parallel responses for nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB (P65)] expression, which specifies that NPAS3 regulates VGF through the NF-κB signaling pathway. Over-expression of NPAS3 also enhances the cell proliferation, which can be blocked by knockdown of VGF. Finally, NPAS3 was found to influence proliferation of neural cells through VGF. Therefore, downstream signaling pathways that are responsible for NPAS3-VGF induced proliferation via glutamate receptors were explored. Combining this work and published literature, a potential network composed by NPAS3, NF-κB, Brain-Derived Neurotrophic Factor (BDNF), NGF and VGF, was proposed. This network collectively detailed how NPAS3 connects with VGF and intersected neural cell proliferation, synaptic activity and psychiatric disorders.

Highlights

Neuronal PAS domain protein 3 (NPAS3) encodes a member of the basic helix-loop-helix PAS domain transcription factor family that typically integrates environmental signals and binds with heterodimeric partner to generate a transcriptional response (Brunskill et al, 1999; Gilles-Gonzalez and Gonzalez, 2004)
Vgf was found to colocalize with Npas3, which suggests that Npas3 might exert its function at the same process in the hippocampus
This study demonstrates that NPAS3 regulates transcription and expression of VGF and delineates that NF-κB signaling pathway is involved in this activation

Summary

Introduction

Neuronal PAS domain protein 3 (NPAS3) encodes a member of the basic helix-loop-helix (bHLH) PAS domain transcription factor family that typically integrates environmental signals and binds with heterodimeric partner to generate a transcriptional response (Brunskill et al, 1999; Gilles-Gonzalez and Gonzalez, 2004). Disruption of the NPAS3 gene carried by a Scottish mother and daughter diagnosed with schizophrenia and mild learning disability provided the first indication of the role of this gene in psychiatric illness (Kamnasaran et al, 2003). Npas knockout mice display a range of behavioral phenotypes consistent with it being a representative model of human psychiatric disorders (Sha et al, 2012). NPAS3 knockout mice display an additional deficit in adult hippocampal neurogenesis and aberrations in synaptic transmissions (Pieper et al, 2005, 2010), but the underlying mechanism of dysfunctions of neurogenesis and synaptic activity in relation to the pathology of psychiatric disorder is currently unknown

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