Role of Per3, a circadian clock gene, in embryonic development of mouse cerebral cortex

Mariko Noda,Koh-Ichi Nagata,Ikuko Iwamoto,Hidenori Ito,Takanori Yamagata,Hidenori Tabata

doi:10.1038/s41598-019-42390-9

Abstract

Per3 is one of the primary components of circadian clock system. While circadian dysregulation is known to be involved in the pathogenesis of several neuropsychiatric diseases. It remains largely unknown whether they participate in embryonic brain development. Here, we examined the role of clock gene Per3 in the development of mouse cerebral cortex. In situ hybridization analysis revealed that Per3 is expressed in the developing mouse cortex. Acute knockdown of Per3 with in utero electroporation caused abnormal positioning of cortical neurons, which was rescued by RNAi-resistant Per3. Per3-deficient cells showed abnormal migration phenotypes, impaired axon extension and dendritic arbor formation. Taken together, Per3 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation.

Highlights

The circadian rhythm is self-sustained oscillations in physiology and behavior with endogenous periods of approximately 24 h, which is controlled by a system of positive and negative feedback loops of clock genes with rhythmic expression patterns in a day[1]
We performed in situ hybridization (ISH) to determine the Per3-mRNA expression in the developing mouse brain
From the results of ISH, we considered that functional defects in Period gene (Per)[3] could induce abnormal brain development which might be related to the etiology of neuropsychiatric diseases

Summary

Introduction

The circadian rhythm is self-sustained oscillations in physiology and behavior with endogenous periods of approximately 24 h, which is controlled by a system of positive and negative feedback loops of clock genes with rhythmic expression patterns in a day[1]. Transcriptional activators, BMAL1 (ARNTL) and CLOCK (or its ortholog NPAS2), form a DNA-binding heterodimer and drive expression of the PER1-3 and CRY1/2 genes, which repress BMAL1-CLOCK activity in a feedback manner. This loop drives rhythmic expression of the nuclear hormone receptors, NR1D1 (Rev-erbα) and NR1D2 (Rev-erbβ), which in turn rhythmically repress the expression of BMAL1 and CLOCK as the second loop[15]. The results obtained indicate that Per[3] plays a crucial role in brain development and its loss-of-function due to haploinsufficiency might contribute to the etiology of neuropsychiatric diseases

Methods

Results

Conclusion