Clock-KO Mouse

Clock, short for Circadian Locomotor Output Cycles Kaput, is a core circadian clock gene. It is fundamental in regulating the circadian rhythm and mediates multiple biological processes. Clock, along with other circadian genes like BMAL1, PER, and CRY, is crucial for the regulation of cellular metabolism. The circadian mechanisms they are involved in may link circadian disruption to adverse metabolic health outcomes such as obesity, metabolic syndrome, and type 2 diabetes [1].

In glioblastoma, a CLOCK-directed circuit promoting tumor angiogenesis has been identified. CLOCK-directed OLFML3 expression leads to HIF1α-mediated upregulation of POSTN, and secreted POSTN promotes tumor angiogenesis via TBK1 signaling in endothelial cells. Blockade of this axis inhibits tumor progression and angiogenesis in mouse and patient-derived xenograft models [2]. In human mesenchymal stem cells (hMSCs), CLOCK expression decreases during aging. CLOCK deficiency accelerates hMSC senescence, while its overexpression rejuvenates aged hMSCs. CLOCK forms complexes with nuclear lamina proteins and KAP1 to maintain heterochromatin architecture, and gene therapy with CLOCK-encoding lentiviral vectors promotes cartilage regeneration and attenuates age-related articular degeneration in mice [3].

In conclusion, Clock is essential for regulating the circadian rhythm and has far-reaching impacts on metabolism, tumor angiogenesis, and stem cell aging and tissue regeneration. Findings from mouse and xenograft models have revealed its role in glioblastoma and age-related articular degeneration, providing potential therapeutic targets for these disease areas.

References:

1. Schrader, Lauren A, Ronnekleiv-Kelly, Sean M, Hogenesch, John B, Bradfield, Christopher A, Malecki, Kristen Mc. 2024. Circadian disruption, clock genes, and metabolic health. In The Journal of clinical investigation, 134, . doi:10.1172/JCI170998. https://pubmed.ncbi.nlm.nih.gov/39007272/

2. Pang, Lizhi, Dunterman, Madeline, Xuan, Wenjing, Heimberger, Amy B, Chen, Peiwen. 2023. Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma. In Cell reports, 42, 112127. doi:10.1016/j.celrep.2023.112127. https://pubmed.ncbi.nlm.nih.gov/36795563/

3. Liang, Chuqian, Liu, Zunpeng, Song, Moshi, Qu, Jing, Liu, Guang-Hui. 2020. Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration. In Cell research, 31, 187-205. doi:10.1038/s41422-020-0385-7. https://pubmed.ncbi.nlm.nih.gov/32737416/