Editors' ChoiceCircadian Biology

Wnt couples the cell cycle to the circadian cycle

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Sci. Signal.  13 Dec 2016:
Vol. 9, Issue 458, pp. ec293
DOI: 10.1126/scisignal.aam5447

Wnt is a signaling protein released by Paneth cells in the intestine to control stem cell and progenitor cell division. Matsu-ura et al. showed that Paneth cells and Wnt signaling also couple the division of these cells to the circadian clock, such that the cells cycle rhythmically and synchronously when grown in culture as mouse enteroids. Enteroids are organoids that self-organize from cultured intestinal stem cells and contain differentiated cells (enterocytes, goblet cells, enteroendocrine cells, and Paneth cells) and dividing, nondifferentiated cells (intestinal stem cells and progenitor cells). When enteroids with cells that expressed markers of the circadian cycle and the cell cycle were generated, the population-level cell cycle was ~12 hours, with the G0-G1 period exhibiting a more variable duration than that of the S-G2-M period. The 12-hour periodicity of the cell cycle depended on the circadian transcription factor Bmal1. Single-cell analysis indicated a more complex pattern with four periodicities: ~9 hours, 13 hours, 19 hours, and 26 hours. To understand how this 4-periodicity pattern produced a single predominating 12-hour cycle at the population level, the authors used a mathematical model containing two populations of cycling cells: intestinal stem cells with a 26-hour cycle and progenitor cells with a 16-hour cycle. Simulations with this model indicated that coupling the cell cycle to the circadian cycle through Wnt reproduced the 12-hour cycle observed in the population. Simulations that coupled the two cycles through the mitosis-inhibiting kinase Wee1 resulted in a periodicity shorter than 12 hours. Furthermore, simulations with Wnt coupling the cell cycle with the circadian cycle predicted that the cells with a cell cycle duration greater than 20 hours had a 1:1 coupling with the circadian cycle (replicating once per circadian cycle), whereas those with a shorter cell cycle duration had a 1:2 coupling with the circadian cycle (replicating twice during the circadian cycle). Cells with the longer cell cycle duration were present in the crypt region, which is where the stem cells and Paneth cells are located. Intestinal stem cells and progenitor cells in the enteroids did not exhibit circadian oscillations of a circadian reporter. In contrast, the mRNA for Wnt3a exhibited circadian oscillations that depended on Bmal1 and Per, the two transcription factors that drive circadian gene expression. Interfering with Wnt signaling so that it could not vary or by ablating the Paneth cells reduced the oscillations in synchronized cell division in the enteroids. Both the cultured enteroids and mouse intestines exhibited fewer crypts when both Per-encoding genes were knocked out. The authors propose a model in which the Paneth cells are the intestinal pacemakers that synchronize the cell cycle division of intestinal stem cells by releasing Wnt in a circadian pattern.

T. Matsu-ura, A. Dovzhenok, E. Aihara, J. Rood, H. Le, Y. Ren, A. E. Rosselot, T. Zhang, C. Lee, K. Obrietan, M. H. Montrose, S. Lim, S. R. Moore, C. I. Hong, Intercellular coupling of the cell cycle and circadian clock in adult stem cell culture. Mol. Cell 64, 900–912 (2016). [PubMed]