The suprachiasmatic nuclei (SCN) of the hypothalamus harbor the central clock of the circadian system, which gradually matures during the perinatal period. In this study, time-resolved transcriptomic and proteomic approaches were used to describe fetal SCN tissue-level rhythms before rhythms in clock gene expression develop. Pregnant rats were maintained in constant darkness and had intact SCN, or their SCN were lesioned and behavioral rhythm was imposed by temporal restriction of food availability. Model-selecting tools dryR and CompareRhythms identified sets of genes in the fetal SCN that were rhythmic in the absence of the fetal canonical clock. Subsets of rhythmically expressed genes were assigned to groups of fetuses from mothers with either intact or lesioned SCN, or both groups. Enrichment analysis for GO terms and signaling pathways revealed that neurodevelopment and cell-to-cell signaling were significantly enriched within the subsets of genes that were rhythmic in response to distinct maternal signals. The findings discovered a previously unexpected breadth of rhythmicity in the fetal SCN at a developmental stage when the canonical clock has not yet developed at the tissue level and thus likely represents responses to rhythmic maternal signals.

Laboratory of Biological Rhythms Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

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Pittendrigh CS, Daan S. Functional-Analysis of Circadian Pacemakers in Nocturnal Rodents.1. Stability and Lability of Spontaneous Frequency. J Comp Physiol. 1976;106(3):223–52. doi: 10.1007/Bf01417856 DOI

Ralph MR, Foster RG, Davis FC, Menaker M. Transplanted suprachiasmatic nucleus determines circadian period. Science. 1990;247(4945):975–8. doi: 10.1126/science.2305266 . PubMed DOI

Pittendrigh CS, Daan S. Functional-Analysis of Circadian Pacemakers in Nocturnal Rodents.4. Entrainment—Pacemaker as Clock. J Comp Physiol. 1976;106(3):291–331. doi: 10.1007/Bf01417859 DOI

Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017;18(3):164–79. Epub 2016/12/19. doi: 10.1038/nrg.2016.150 . PubMed DOI PMC

Hastings MH, Maywood ES, Brancaccio M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci 2018;19(8):453–69. Epub 2018/06/24. doi: 10.1038/s41583-018-0026-z . PubMed DOI

Welsh DK, Takahashi JS, Kay SA. Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol 2010;72:551–77. Epub 2010/02/13. doi: 10.1146/annurev-physiol-021909-135919 . PubMed DOI PMC

Moore RY. Development of the suprachiasmatic nucleus. In: Klein DC, Moore RY, Reppert SM, editors. Suprachiasmatic Nucleus: the Mind’s Clock. New York: Oxford University Press; 1991. p. 197–216.

Fuchs JL, Moore RY. Development of circadian rhythmicity and light responsiveness in the rat suprachiasmatic nucleus: a study using the 2-deoxy[1-14C]glucose method. Proc Natl Acad Sci U S A. 1980;77(2):1204–8. doi: 10.1073/pnas.77.2.1204 . PubMed DOI PMC

Landgraf D, Koch CE, Oster H. Embryonic development of circadian clocks in the mammalian suprachiasmatic nuclei. Front Neuroanat. 2014;8:143. Epub 2014/12/19. doi: 10.3389/fnana.2014.00143 . PubMed DOI PMC

Bedont JL, Blackshaw S. Constructing the suprachiasmatic nucleus: a watchmaker’s perspective on the central clockworks. Front Syst Neurosci. 2015;9:74. Epub 2015/05/26. doi: 10.3389/fnsys.2015.00074 . PubMed DOI PMC

Moore RY, Bernstein ME. Synaptogenesis in the rat suprachiasmatic nucleus demonstrated by electron microscopy and synapsin I immunoreactivity. J Neurosci 1989;9(6):2151–62. Epub 1989/06/01. doi: 10.1523/JNEUROSCI.09-06-02151.1989 . PubMed DOI PMC

Welsh DK, Logothetis DE, Meister M, Reppert SM. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron. 1995;14(4):697–706. doi: 10.1016/0896-6273(95)90214-7 . PubMed DOI

Sladek M, Sumova A, Kovacikova Z, Bendova Z, Laurinova K, Illnerova H. Insight into molecular core clock mechanism of embryonic and early postnatal rat suprachiasmatic nucleus. Proc Natl Acad Sci U S A. 2004;101(16):6231–6. doi: 10.1073/pnas.0401149101 . PubMed DOI PMC

Kovacikova Z, Sladek M, Bendova Z, Illnerova H, Sumova A. Expression of clock and clock-driven genes in the rat suprachiasmatic nucleus during late fetal and early postnatal development. J Biol Rhythms. 2006;21(2):140–8. doi: 10.1177/0748730405285876 . PubMed DOI

Ansari N, Agathagelidis M, Lee C, Korf HW, von Gall C. Differential maturation of circadian rhythms in clock gene proteins in the suprachiasmatic nucleus and the pars tuberalis during mouse ontogeny. Eur J Neurosci. 2009;29(3):477–89. Epub 2009/02/19. doi: 10.1111/j.1460-9568.2008.06605.x . PubMed DOI PMC

Li X, Davis FC. Developmental expression of clock genes in the Syrian hamster. Brain Res Dev Brain Res. 2005;158(1–2):31–40. Epub 2005/07/01. doi: 10.1016/j.devbrainres.2005.05.005 . PubMed DOI

Sumova A, Cecmanova V. Mystery of rhythmic signal emergence within the suprachiasmatic nuclei. Eur J Neurosci. 2018. Epub 2018/09/07. doi: 10.1111/ejn.14141 . PubMed DOI

Carmona-Alcocer V, Abel JH, Sun TC, Petzold LR, Doyle FJ 3rd, Simms CL, et al.. Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus. J Neurosci. 2018;38(6):1326–34. Epub 2017/10/22. doi: 10.1523/JNEUROSCI.2006-17.2017 . PubMed DOI PMC

Landgraf D, Achten C, Dallmann F, Oster H. Embryonic development and maternal regulation of murine circadian clock function. Chronobiol Int. 2014:1–12. Epub 2014/11/29. doi: 10.3109/07420528.2014.986576 . PubMed DOI

Wreschnig D, Dolatshad H, Davis FC. Embryonic development of circadian oscillations in the mouse hypothalamus. J Biol Rhythms. 2014;29(4):299–310. Epub 2014/09/23. 29/4/299 doi: 10.1177/0748730414545086 . PubMed DOI

Cecmanova V, Houdek P, Suchmanova K, Sladek M, Sumova A. Development and Entrainment of the Fetal Clock in the Suprachiasmatic Nuclei: The Role of Glucocorticoids. J Biol Rhythms. 2019;34(3):307–22. Epub 2019/03/12. doi: 10.1177/0748730419835360 . PubMed DOI

Yoshikawa T, Yamazaki S, Menaker M. Effects of preparation time on phase of cultured tissues reveal complexity of circadian organization. J Biol Rhythms. 2005;20(6):500–12. Epub 2005/11/09. 20/6/500 doi: 10.1177/0748730405280775 . PubMed DOI PMC

Houdek P, Sumova A. In Vivo Initiation of Clock Gene Expression Rhythmicity in Fetal Rat Suprachiasmatic Nuclei. PLoS ONE [Internet]. 2014;9(9):[e107360 p.]. doi: 10.1371/journal.pone.0107360 PubMed DOI PMC

Reppert SM, Schwartz WJ. Maternal coordination of the fetal biological clock in utero. Science. 1983;220(4600):969–71. doi: 10.1126/science.6844923 . PubMed DOI

Reppert SM, Schwartz WJ. The suprachiasmatic nuclei of the fetal rat: characterization of a functional circadian clock using 14C-labeled deoxyglucose. J Neurosci. 1984;4(7):1677–82. doi: 10.1523/JNEUROSCI.04-07-01677.1984 . PubMed DOI PMC

Reppert SM, Uhl GR. Vasopressin messenger ribonucleic acid in supraoptic and suprachiasmatic nuclei: appearance and circadian regulation during development. Endocrinology. 1987;120(6):2483–7. doi: 10.1210/endo-120-6-2483 . PubMed DOI

Shibata S, Moore RY. Development of neuronal activity in the rat suprachiasmatic nucleus. Brain Res. 1987;431(2):311–5. doi: 10.1016/0165-3806(87)90220-3 . PubMed DOI

Luzna V, Houdek P, Liska K, Sumova A. Challenging the Integrity of Rhythmic Maternal Signals Revealed Gene-Specific Responses in the Fetal Suprachiasmatic Nuclei. Front Neurosci. 2020;14:613531. Epub 2021/01/26. doi: 10.3389/fnins.2020.613531 . PubMed DOI PMC

Sumova A, Sladek M, Polidarova L, Novakova M, Houdek P. Circadian system from conception till adulthood. Prog Brain Res. 2012;199:83–103. doi: 10.1016/B978-0-444-59427-3.00005-8 . PubMed DOI

Weinert D. Ontogenetic development of the mammalian circadian system. Chronobiol Int. 2005;22(2):179–205. doi: 10.1081/cbi-200053473 . PubMed DOI

Sumova A, Bendova Z, Sladek M, El-Hennamy R, Laurinova K, Jindrakova Z, et al.. Setting the biological time in central and peripheral clocks during ontogenesis. FEBS Lett. 2006;580(12):2836–42. doi: 10.1016/j.febslet.2006.03.023 . PubMed DOI

El-Hennamy R, Mateju K, Bendova Z, Sosniyenko S, Sumova A. Maternal control of the fetal and neonatal rat suprachiasmatic nucleus. J Biol Rhythms. 2008;23(5):435–44. Epub 2008/10/08. 23/5/435 doi: 10.1177/0748730408322635 . PubMed DOI

Weger BD, Gobet C, David FPA, Atger F, Martin E, Phillips NE, et al.. Systematic analysis of differential rhythmic liver gene expression mediated by the circadian clock and feeding rhythms. Proc Natl Acad Sci U S A. 2021;118(3). Epub 2021/01/17. doi: 10.1073/pnas.2015803118 . PubMed DOI PMC

Pelikan A, Herzel H, Kramer A, Ananthasubramaniam B. Venn diagram analysis overestimates the extent of circadian rhythm reprogramming. FEBS J. 2021. Epub 2021/07/01. doi: 10.1111/febs.16095 . PubMed DOI

Houdek P, Polidarova L, Novakova M, Mateju K, Kubik S, Sumova A. Melatonin administered during the fetal stage affects circadian clock in the suprachiasmatic nucleus but not in the liver. Dev Neurobiol. 2015;75(2):131–44. Epub 2014/07/22. doi: 10.1002/dneu.22213 . PubMed DOI

Viswanathan N, Davis FC. Single prenatal injections of melatonin or the D1-dopamine receptor agonist SKF 38393 to pregnant hamsters sets the offsprings’ circadian rhythms to phases 180 degrees apart. J Comp Physiol A 1997;180(4):339–46. Epub 1997/04/01. doi: 10.1007/s003590050053 . PubMed DOI

Bates K, Herzog ED. Maternal-Fetal Circadian Communication During Pregnancy. Front Endocrinol (Lausanne). 2020;11:198. Epub 2020/05/01. doi: 10.3389/fendo.2020.00198 . PubMed DOI PMC

Ono D, Honma KI, Honma S. Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock. Front Neurosci. 2021;15:650154. Epub 2021/05/04. doi: 10.3389/fnins.2021.650154 . PubMed DOI PMC

Novakova M, Sladek M, Sumova A. Exposure of pregnant rats to restricted feeding schedule synchronizes the SCN clocks of their fetuses under constant light but not under a light-dark regime. J Biol Rhythms. 2010;25(5):350–60. Epub 2010/09/30. 25/5/350 doi: 10.1177/0748730410377967 . PubMed DOI

Olejnikova L, Polidarova L, Behuliak M, Sladek M, Sumova A. Circadian alignment in a foster mother improves the offspring’s pathological phenotype. J Physiol. 2018;596(23):5757–75. Epub 2018/05/12. doi: 10.1113/JP275585 . PubMed DOI PMC

Olejnikova L, Polidarova L, Pauslyova L, Sladek M, Sumova A. Diverse development and higher sensitivity of the circadian clocks to changes in maternal-feeding regime in a rat model of cardio-metabolic disease. Chronobiol Int. 2015;32(4):531–47. doi: 10.3109/07420528.2015.1014095 PubMed DOI

Deery MJ, Maywood ES, Chesham JE, Sladek M, Karp NA, Green EW, et al.. Proteomic analysis reveals the role of synaptic vesicle cycling in sustaining the suprachiasmatic circadian clock. Curr Biol. 2009;19(23):2031–6. Epub 2009/11/17. doi: 10.1016/j.cub.2009.10.024 . PubMed DOI

Robles MS, Cox J, Mann M. In-vivo quantitative proteomics reveals a key contribution of post-transcriptional mechanisms to the circadian regulation of liver metabolism. PLoS Genet. 2014;10(1):e1004047. Epub 2014/01/07. doi: 10.1371/journal.pgen.1004047 . PubMed DOI PMC

Mauvoisin D, Wang J, Jouffe C, Martin E, Atger F, Waridel P, et al.. Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver. Proc Natl Acad Sci U S A. 2014;111(1):167–72. Epub 2013/12/18. doi: 10.1073/pnas.1314066111 . PubMed DOI PMC

Chiang CK, Mehta N, Patel A, Zhang P, Ning Z, Mayne J, et al.. The proteomic landscape of the suprachiasmatic nucleus clock reveals large-scale coordination of key biological processes. PLoS Genet. 2014;10(10):e1004695. Epub 2014/10/21. doi: 10.1371/journal.pgen.1004695 . PubMed DOI PMC

Mendoza-Viveros L, Chiang CK, Ong JLK, Hegazi S, Cheng AH, Bouchard-Cannon P, et al.. miR-132/212 Modulates Seasonal Adaptation and Dendritic Morphology of the Central Circadian Clock. Cell Rep. 2017;19(3):505–20. Epub 2017/04/20. doi: 10.1016/j.celrep.2017.03.057 . PubMed DOI PMC

Robles MS, Humphrey SJ, Mann M. Phosphorylation Is a Central Mechanism for Circadian Control of Metabolism and Physiology. Cell Metab. 2017;25(1):118–27. Epub 2016/11/08. doi: 10.1016/j.cmet.2016.10.004 . PubMed DOI

Agostinelli F, Ceglia N, Shahbaba B, Sassone-Corsi P, Baldi P. What time is it? Deep learning approaches for circadian rhythms. Bioinformatics. 2016;32(12):i8–i17. Epub 2016/06/17. doi: 10.1093/bioinformatics/btw243 . PubMed DOI PMC

Hutchison AL, Maienschein-Cline M, Chiang AH, Tabei SM, Gudjonson H, Bahroos N, et al.. Improved statistical methods enable greater sensitivity in rhythm detection for genome-wide data. PLoS Comput Biol. 2015;11(3):e1004094. Epub 2015/03/21. doi: 10.1371/journal.pcbi.1004094 . PubMed DOI PMC

Wu G, Anafi RC, Hughes ME, Kornacker K, Hogenesch JB. MetaCycle: an integrated R package to evaluate periodicity in large scale data. Bioinformatics. 2016;32(21):3351–3. Epub 2016/10/30. doi: 10.1093/bioinformatics/btw405 . PubMed DOI PMC

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al.. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. Epub 2019/04/05. doi: 10.1038/s41467-019-09234-6 . PubMed DOI PMC

The circadian clock in the choroid plexus drives rhythms in multiple cellular processes under the control of the suprachiasmatic nucleus

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