Maternal high-fat diet is associated with impaired fetal lung development.

Maternal nutrition has a profound long-term impact on infant health. Poor maternal nutrition influences placental development and fetal growth, resulting in low birth weight, which is strongly associated with the risk of developing chronic diseases, including heart disease, hypertension, asthma, and type 2 diabetes, later in life. Few studies have delineated the mechanisms by which maternal nutrition affects fetal lung development. Here, we report that maternal exposure to a diet high in fat (HFD) causes placental inflammation, resulting in placental insufficiency, fetal growth restriction (FGR), and inhibition of fetal lung development. Notably, pre- and postnatal exposure to maternal HFD also results in persistent alveolar simplification in the postnatal period. Our novel findings provide a strong association between maternal diet and fetal lung development.

The Neurospora crassa OS MAPK pathway-activated transcription factor ASL-1 contributes to circadian rhythms in pathway responsive clock-controlled genes.

The OS-pathway mitogen-activated protein kinase (MAPK) cascade of Neurospora crassa is responsible for adaptation to osmotic stress. Activation of the MAPK, OS-2, leads to the transcriptional induction of many genes involved in the osmotic stress response. We previously demonstrated that there is a circadian rhythm in the phosphorylation of OS-2 under constant non-stress inducing conditions. Additionally, several osmotic stress-induced genes are known to be regulated by the circadian clock. Therefore, we investigated if rhythms in activation of OS-2 lead to circadian rhythms in other known stress responsive targets. Here we identify three more osmotic stress induced genes as rhythmic: cat-1, gcy-1, and gcy-3. These genes encode a catalase and two predicted glycerol dehydrogenases thought to be involved in the production of glycerol. Rhythms in these genes depend upon the oscillator component FRQ. To investigate how the circadian signal is propagated to these stress induced genes, we examined the role of the OS-responsive transcription factor, ASL-1, in mediating circadian gene expression. We find that while the asl-1 transcript is induced by several stresses including an osmotic shock, asl-1 mRNA accumulation is not rhythmic. However, we show that ASL-1 is required for generating normal circadian rhythms of some OS-pathway responsive transcripts (bli-3, ccg-1, cat-1, gcy-1 and gcy-3) in the absence of an osmotic stress. These data are consistent with the possibility that post-transcriptional regulation of ASL-1 by the rhythmically activated OS-2 MAPK could play a role in generating rhythms in downstream targets.

Direct transcriptional control of a p38 MAPK pathway by the circadian clock in Neurospora crassa.

MAPK signal transduction pathways are important regulators of stress responses, cellular growth, and differentiation. In Neurospora, the circadian clock controls rhythms in phosphorylation of the p38-like MAPK (OS-2); however, the mechanism for this regulation is not known. We show that the WCC, a transcription factor and clock component, binds to the os-4 MAPKKK promoter in response to light and rhythmically in constant darkness, peaking in the subjective morning. Deletion of the WCC binding sites in the os-4 promoter disrupts both os-4 mRNA and OS-2 phosphorylation rhythms. The clock also indirectly regulates rhythmic expression of the histidyl-phosphotransferase gene, hpt-1, which peaks in the evening. Anti-phase expression of positive (OS-4) and negative (HPT-1) MAPK pathway regulators likely coordinate to enhance rhythmic MAPK activation to prepare cells to respond to osmotic stress during the day in the natural environment. Consistent with this idea, we show that wild type cells have a clock-dependent morning kinetic advantage in glycerol accumulation after salt stress as compared to evening treatment. Thus, circadian transcriptional control of MAPK pathway components leads to striking time-of-day-specific effects on the signaling status and physiological response of the pathway.