A new study uses time-resolved transcriptomic and proteomic data from fetal cells of the suprachiasmatic nucleus (SCN)—the master circadian clock in the hypothalamus of the brain—in rat models, to discover widespread genetic rhythmicity before the SCN develops the ability to keep time. The researchers claim these early rhythms of the fetal SCN receive their cues from maternal signals.

The study led by Alena Sumová, PhD, DSc, an associate professor and head of the laboratory of biological rhythms at the Institute of Physiology at the Czech Academy of Sciences, was published in an article in the journal PLOS Biology titled, “Early rhythmicity in the fetal suprachiasmatic nuclei in response to maternal signals detected by omics approach.” The findings add to the mechanistic understanding of the development of the human biological clock and could lead to new approaches to treating premature births.

“The current study pioneers the identification of fetal SCN responses to distinct maternal rhythmic signals through analyses of transcriptomic and proteomic data in fetal SCN samples collected around the clock at a developmental stage when cell population rhythms in clock gene expression have not yet developed,” the authors noted.

Sumová added, “Our study reveals that distinct maternal signals rhythmically control a variety of neuronal processes in the fetal rat suprachiasmatic nuclei before they begin to operate as the central circadian clock. The results indicate the importance of a well-functioning maternal biological clock in providing a rhythmic environment during the fetal brain development.”

The rhythmic expression of genes in the SCN governs the periodic activity of other genes in the body both local and distant, influencing a variety of circadian behaviors, such as sleep-wake cycles and feeding patterns. However, earlier studies on rodent models show that the fetal SCN develops its own genetic rhythms only a day or two before birth.

Although earlier evidence suggests developing SCN clocks are reset by maternal signals and respond to disruptions in maternal rhythms when the fetal SCN clock has not yet developed, the extent of rhythmicity in the fetal SCN in response to rhythmic maternal signals was not clear.

To determine whether the fetal SCN exhibits rhythmicity in cellular processes at developmental stages before the SCN master clock develops and whether such rhythmic processes require the presence of a functional maternal SCN or respond to systemic rhythms, the researchers in the current study compared patterns of gene activity in SCN tissue from fetuses of pregnant rats kept in constant darkness to remove the effect of environmental cues.

A subset of these pregnant rats kept in constant darkness had intact SCNs and free access to food. The other subset of pregnant rats had their SCN disrupted and had access to food only for eight hours a day, to impose a daily rhythm on their activity.

Using biostatistical tools such as dryR and CompareRhythms, the team identified groups of genes in the fetal SCN that were rhythmically expressed before the establishment of the SCN clock. The investigators observed a small set of genes whose timing of expression differed between fetal SCNs of the two groups and a larger gene set where the timing pattern oscillated synchronously in the two groups.

“Our transcriptomic results provide novel insights into the previously unnoticed scope and diversity of rhythmically expressed genes in the fetal SCN just before cell population rhythms in locally expressed clock genes start to manifest coherently,” the authors noted.

Using gene ontology enrichment analysis (GO analysis), the researchers found that many of the genes that responded to maternal signaling cues were genes important in neuronal development and signaling.

“Our data reveal that in development in the fetal suprachiasmatic nuclei, maternal stimuli may substitute for an absent inter-cellular web of synapses and drive cell-population rhythms before the SCN clock fully matures,” Sumová said.

Rats have a gestational period of about 21 days. In this study, the fetuses were examined at 19 days post conception. These results may therefore have implications for premature human babies, Sumová added.

“The unexpected broadness and specificity of responsiveness of the SCN cells to maternal signals stresses the importance of a healthy maternal circadian system during pregnancy and points at the potential impact of the absence of such signals in prematurely delivered children,” the authors noted.

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