Transcriptional regulation of the mouse EphA4 , Ephrin-B2 and Ephrin-A3 genes by the circadian clock machinery

Aug 8, 2023Chronobiology international

Daily rhythms control activity of mouse genes for EphA4, Ephrin-B2, and Ephrin-A3

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Abstract

CLOCK and BMAL1 may regulate the gene expression of EPHA4 and EFNB2, impacting circadian rhythms.

Circadian rhythms are influenced by molecular feedback loops involving transcription factors.
CLOCK and BMAL1 activate E-boxes in the genes of EPHA4 and EFNB2.
A mutant form of glycogen synthase kinase 3β inhibited the transcriptional activity of CLOCK and BMAL1.
Mutations in E-boxes of the distal promoter sequence decreased transcriptional induction.
EPHA4 and EFNB2 protein levels did not exhibit circadian variations in key brain regions.

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Circadian rhythms originate from molecular feedback loops. In mammals, the transcription factors CLOCK and BMAL1 act on regulatory elements (i.e. E-boxes) to shape biological functions in a rhythmic manner. The EPHA4 receptor and its ligands Ephrins (EFN) are cell adhesion molecules regulating neurotransmission and neuronal morphology. Previous studies showed the presence of E-boxes in the genes ofand specific Ephrins, and thatknockout mice have an altered circadian rhythm of locomotor activity. We thus hypothesized that the core clock machinery regulates the gene expression of,and. CLOCK and BMAL1 (or NPAS2 and BMAL2) were found to have transcriptional activity on distal and proximal regions of,andputative promoters. A constitutively active form of glycogen synthase kinase 3β (GSK3β; a negative regulator of CLOCK and BMAL1) blocked the transcriptional induction. Mutating the E-boxes ofdistal promoter sequence reduced transcriptional induction. EPHA4 and EFNB2 protein levels did not show circadian variations in the mouse suprachiasmatic nucleus or prefrontal cortex. The findings uncover that core circadian transcription factors can regulate the gene expression of elements of the Eph/Ephrin system, which might contribute to circadian rhythmicity in biological processes in the brain or peripheral tissues. EphA4EphA4EphA4EfnB2EfnA3EphA4EfnB2EfnA3EphA4

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Transcriptional regulation of the mouse EphA4 , Ephrin-B2 and Ephrin-A3 genes by the circadian clock machinery

Abstract

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