Reciprocal regulation between autism risk gene POGZ and circadian clock
Ting Wu, Jiao He, Chu-Jun Xu, Chi-Yu Li, Pingchuan Zhang, Yanfeng Wang, Shanshan Zhu, Lusi Zhang, Jingtan Zhu, Jing Zhang, Jia-Da Li, Huadie Liu
Ting Wu, Jiao He, Chu-Jun Xu, Chi-Yu Li, Pingchuan Zhang, Yanfeng Wang, Shanshan Zhu, Lusi Zhang, Jingtan Zhu, Jing Zhang, Jia-Da Li, Huadie Liu
View: Text | PDF
Research Article Development Genetics Neuroscience

Reciprocal regulation between autism risk gene POGZ and circadian clock

Abstract

Sleep disturbance is a prevalent yet poorly understood comorbidity in autism spectrum disorders (ASD). Here, we uncover a bidirectional regulatory axis connecting the ASD risk gene POGZ to core circadian mechanisms. We demonstrate that Pogz is widely expressed in the suprachiasmatic nucleus (SCN), the central pacemaker of the circadian rhythms, and exhibits circadian oscillations in both the hypothalamus and liver, with its transcription directly regulated by the circadian molecule DBP through a D-box element in its proximal enhancer. Pogz-deficient mice exhibited prolonged circadian periodicity, impaired light-induced phase shift, delayed adaption to an 8-hour advance jet-lag, and reduced SCN c-Fos activation in response to light pulses. Mechanistically, POGZ interacts with and enhances the transcription activity of CREB, a key regulator of light-induced phase resetting. Notably, Pogz deletion leads to ASD-related deficits in social novelty and cognition, with cognitive impairments influenced by both photoperiod and behavioral paradigm. Our findings, thus, reveal a critical, previously unrecognized intersection between an ASD risk gene and circadian clock, offering insights into the pathogenesis of core ASD symptoms and comorbid sleep disturbances.

Authors

Ting Wu, Jiao He, Chu-Jun Xu, Chi-Yu Li, Pingchuan Zhang, Yanfeng Wang, Shanshan Zhu, Lusi Zhang, Jingtan Zhu, Jing Zhang, Jia-Da Li, Huadie Liu

×

Figure 4

Pogz-deficient mice are defective in resetting the circadian clock.

Options: View larger image (or click on image) Download as PowerPoint
Pogz-deficient mice are defective in resetting the circadian clock. (A ...
(A and B) Phase delays in response to a 15-minute light pulse (LP) at CT15 in Pogzfl/fl (Ctrl), Pogz nKO (A) and Pogz iKO (B). Representative actograms (left) and phase delay quantifications (Right, n = 5–8 per group) are presented. (C) Locomotor activity in Pogzfl/fl (Ctrl) and Pogz-nKO mice during a 4-h light exposure administered at night (ZT15–ZT19). Representative actograms (left) and quantification of light masking responses shown as the percentage reduction in activity during the 4-h light pulse compared with the same period over the previous 5 days under LD (right) are included. (D) Phase-shift adaptation test in a simulated jet-lag paradigm of Pogzfl/fl (Ctrl) and Pogz-nKO mice. Representative actograms (left), group analysis of activity onset in Pogzfl/fl (Ctrl) and Pogz nKO mice (n = 6–7 per group) (middle), and PS50 value (time to reach 50% phase shift) for Pogzfl/fl (Ctrl) and Pogz nKO mice (right) are included. White background indicates the lights-on condition, while the gray background indicates the lights-off condition in representative actograms of A–D. (E) Whole-brain c-Fos labeling and SCN quantification. Representative optical sections of 3D-rendered c-Fos+ cells in the whole brain and SCN from WT and Pogz nKO mice, under baseline or light-pulse (LP) conditions (left) and quantification of c-Fos+ cells in the bilateral SCN under the same conditions (right), are included (n = 3 for each group). All data in this figure are shown as mean ± SEM. Comparisons in A–D (right) are conducted using unpaired 2-tailed Student’s t test, in D (middle) are conducted 2-way ANOVA, and in E are conducted 1-way ANOVA. ***P < 0.001; **P < 0.01; *P < 0.05.