It’s about time: clocks in the developing lung
Colleen M. Bartman, … , Aleksey Matveyenko, Y.S. Prakash
Colleen M. Bartman, … , Aleksey Matveyenko, Y.S. Prakash
Published January 2, 2020
Citation Information: J Clin Invest. 2020;130(1):39-50. https://doi.org/10.1172/JCI130143.
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It’s about time: clocks in the developing lung

Abstract

The discovery of peripheral intracellular clocks revealed circadian oscillations of clock genes and their targets in all cell types, including those in the lung, sparking exploration of clocks in lung disease pathophysiology. While the focus has been on the role of these clocks in adult airway diseases, clock biology is also likely to be important in perinatal lung development, where it has received far less attention. Historically, fetal circadian rhythms have been considered irrelevant owing to lack of external light exposure, but more recent insights into peripheral clock biology raise questions of clock emergence, its concordance with tissue-specific structure/function, the interdependence of clock synchrony and functionality in perinatal lung development, and the possibility of lung clocks in priming the fetus for postnatal life. Understanding the perinatal molecular clock may unravel mechanistic targets for chronic airway disease across the lifespan. With current research providing more questions than answers, it is about time to investigate clocks in the developing lung.

Authors

Colleen M. Bartman, Aleksey Matveyenko, Y.S. Prakash

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Figure 1

Factors during fetal development and throughout life that drive progression of chronic airway disease and potential role of the clock’s transcription-translation 24-hour feedback loop.

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Factors during fetal development and throughout life that drive progress...
(A) During fetal development, maternal signals (e.g., stress hormones, hormonal factors), fetal nutrition, premature birth, genetic predisposition, and perhaps the clock influence development of chronic airway disease. Additionally, environmental factors, infections, and the clock during postnatal life and during adulthood further drive airway disease, defined by airway hyperreactivity, infectious susceptibility, airway remodeling, inflammation, and altered contractility. (B) The relationship between the clock and developmental pathways may prime the fetal lung for postnatal life. BMAL1 and CLOCK drive expression of PER and CRY genes. PERs and CRYs, which are posttranslationally modified in the cytoplasm, heterodimerize and translocate back to the nucleus, where they inhibit the BMAL1-CLOCK complex, thereby suppressing their own gene expression. This pattern occurs such that BMAL1 and CLOCK peak during the nighttime, while PERs and CRYs peak in the morning. The nuclear receptors REV-ERBs inhibit BMAL1 (Arntl) gene expression, while RORs drive Arntl gene expression. Key pathways involved in fetal lung development have a bidirectional relationship with the molecular clock. Core clock components are shown in blue, lung developmental pathways in orange, secondary messengers in purple, non-clock proteins in red, and inflammatory or antioxidant pathways in green. Genes and gene targets are styled in italics.