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The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.

Parsons MJ, Brancaccio M, Sethi S, Maywood ES, Satija R, Edwards JK, Jagannath A, Couch Y, Finelli MJ, Smyllie NJ, Esapa C, Butler R, Barnard AR, Chesham JE, Saito S, Joynson G, Wells S, Foster RG, Oliver PL, Simon MM, Mallon AM, Hastings MH, Nolan PM - Cell (2015)

Bottom Line: Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3(Sci/+) SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed.Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3(Sci/+) SCN slices.In conclusion, by cloning Zfhx3(Sci), we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

View Article: PubMed Central - PubMed

Affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.

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Model Depicting the Role of the ZFHX3/AT Axis in Maintaining SCN OscillationsA diagram outlining the proposed mechanism for maintaining robust circadian oscillations in the SCN. The ZFHX3/AT axis is sensitive to the TTFL and, in turn, feeds back temporal information to the TTFL through its neuropeptidergic-dependent effects on intercellular, circuit-level signaling.
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fig7: Model Depicting the Role of the ZFHX3/AT Axis in Maintaining SCN OscillationsA diagram outlining the proposed mechanism for maintaining robust circadian oscillations in the SCN. The ZFHX3/AT axis is sensitive to the TTFL and, in turn, feeds back temporal information to the TTFL through its neuropeptidergic-dependent effects on intercellular, circuit-level signaling.

Mentions: It is clear from our results that the period of AT-driven transcription is sensitive to the period of the TTFL, as evidenced by the effect of CK1 inhibition. This argues that the ZFHX3/AT axis is downstream of the TTFL. However, it is also affected by the Zfhx3Sci mutation, as is the period of the TTFL, as reported by PER expression. The TTFL and AT axes are, therefore, reciprocally dependent, each able to influence the other. We propose that this arises from the circuit-level effects of AT-driven transcription, specifically of neuropeptide-encoding genes, leading to a logical module in which the TTFL affects AT function. In turn, AT motif activation affects neuropeptidergic expression, leading to cell-nonautonomous effects on circuit-level signaling in the SCN, and ultimately influences TTFL activity (FigureĀ 7).


The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.

Parsons MJ, Brancaccio M, Sethi S, Maywood ES, Satija R, Edwards JK, Jagannath A, Couch Y, Finelli MJ, Smyllie NJ, Esapa C, Butler R, Barnard AR, Chesham JE, Saito S, Joynson G, Wells S, Foster RG, Oliver PL, Simon MM, Mallon AM, Hastings MH, Nolan PM - Cell (2015)

Model Depicting the Role of the ZFHX3/AT Axis in Maintaining SCN OscillationsA diagram outlining the proposed mechanism for maintaining robust circadian oscillations in the SCN. The ZFHX3/AT axis is sensitive to the TTFL and, in turn, feeds back temporal information to the TTFL through its neuropeptidergic-dependent effects on intercellular, circuit-level signaling.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4537516&req=5

fig7: Model Depicting the Role of the ZFHX3/AT Axis in Maintaining SCN OscillationsA diagram outlining the proposed mechanism for maintaining robust circadian oscillations in the SCN. The ZFHX3/AT axis is sensitive to the TTFL and, in turn, feeds back temporal information to the TTFL through its neuropeptidergic-dependent effects on intercellular, circuit-level signaling.
Mentions: It is clear from our results that the period of AT-driven transcription is sensitive to the period of the TTFL, as evidenced by the effect of CK1 inhibition. This argues that the ZFHX3/AT axis is downstream of the TTFL. However, it is also affected by the Zfhx3Sci mutation, as is the period of the TTFL, as reported by PER expression. The TTFL and AT axes are, therefore, reciprocally dependent, each able to influence the other. We propose that this arises from the circuit-level effects of AT-driven transcription, specifically of neuropeptide-encoding genes, leading to a logical module in which the TTFL affects AT function. In turn, AT motif activation affects neuropeptidergic expression, leading to cell-nonautonomous effects on circuit-level signaling in the SCN, and ultimately influences TTFL activity (FigureĀ 7).

Bottom Line: Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3(Sci/+) SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed.Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3(Sci/+) SCN slices.In conclusion, by cloning Zfhx3(Sci), we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.

View Article: PubMed Central - PubMed

Affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK.

Show MeSH