Biology subjects

Koike, N.

Publications and source records attributed to Koike, N..

5 recordsLinked to original sources

bioRxiv2026

Cryptochrome Loss Drives COPD-like Lung Pathology through Disrupted Alveolar Epithelial Proliferation and Immune Homeostasis

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by alveolar destruction, impaired epithelial regeneration and chronic inflammation. While circadian disruption has been linked to COPD pathogenesis, the cellular mechanisms remain unclear. Here, we identify the core clock components Cryptochrome 1 and 2 (Cry1/2) as essential regulators of alveolar epithelial cell proliferation and pulmonary immune homeostasis. Cry1/2 double knockout (dKO) mice exhibit spontaneous emphysema-like pathology, including airspace enlargement, increased lung compliance, and inflammatory cell infiltration without environmental insults. Mechanistically, Cry1/2-deficient alveolar epithelial cells display reduced proliferative capacity, and transcriptomic profiling revealed a pronounced shift toward a more proximal airway-like phenotype. Notably, these cells share a gene signature with human COPD lungs in pathways involving immune regulation. Furthermore, Cry1/2-deficient macrophages show elevated responsiveness to LPS. Bone marrow (BM) transplantation revealed that mice receiving Cry1/2 dKO BM suffer from enhanced lung inflammation without airspace enlargement, supporting a critical role of epithelial Cry1/2 in maintaining alveolar integrity. Importantly, treatment with Nobiletin, a circadian rhythm-modulating compound, mitigates NF-{kappa}B activation and ameliorates lung inflammation and structural damage in Cry1/2 dKO mice. These findings establish CRY1/2 as critical circadian regulators of epithelial cell proliferation and immune homeostasis, and highlight the therapeutic potential of targeting circadian pathways in COPD.

genetics↗

bioRxiv2026

11β-HSD2 buffers fetal glucocorticoid exposure inducing Per1 expression under maternal stress

Glucocorticoids (GCs) have been proposed as maternal-fetal communication signals. However, fetal circadian rhythms are initially shielded from maternal entrainment, in addition to delayed circadian clock emergence due to CLOCK suppression. Premature CLOCK/BMAL1 activation disrupts Hes7-driven somite-like structure in gastruloids. Given the genomic proximity of Per1 to Hes7 and their transcriptional ripple effect, the physiological significance of delayed cell-autonomous circadian clock development and the temporal program of maternal-fetal communication during the developmental process have remained unclear. Here, based on a marked decline in Hsd11b2, encoding a GC-inactivating 11{beta}-HSD2 enzyme, during organogenesis, we performed split-litter embryo-transfer experiments in which Hsd11b2 knockout (KO) and wild-type (WT) embryos shared the same maternal environment. Amniotic fluid (AF) GCs remained low and arrhythmic under basal conditions. In contrast, maternal stress caused a pronounced GC surge and Per1 induction in KO, suggesting that 11{beta}-HSD2 buffers acute maternal GC surges. Despite the genomic proximity of Per1 to Hes7 and their transcriptional ripple effect, stress-associated and pharmacological GC exposure recapitulated no overt segmentation defects in vivo. Embryonic stem cell-derived gastruloid assays confirmed that neither GC exposure nor Per1 induction arrested Hes7 oscillations, whereas premature CLOCK/BMAL1 activation impaired these processes even in Hes7 KO gastruloid with ectopic rescue, suggesting that interference with the segmentation clock is mediated by premature CLOCK/BMAL1 activation, not by GC-induced Per1 expression. These findings clearly show that maternal GC signals are selectively buffered during early development. In addition, suppression of CLOCK/BMAL1 activity preserves segmentation clock function, indicating delayed circadian clock emergence is actively regulated during embryogenesis. Significance StatementGCs have been proposed as maternal-fetal communication signals. However, initially, circadian clock is not only suppressed but also shielded from maternal entrainment. Premature CLOCK/BMAL1 activation can disrupt Hes7-driven somitogenesis. In a split-litter Hsd11b2-knockout model, AF GCs remained low and arrhythmic basally but surged after maternal stress in KO embryos, inducing Per1. Despite a genomic position effect of Per1-Hes7 and their putative transcriptional coupling, stress-associated or pharmacological GC exposure did not cause segmentation defects in vivo or disrupt Hes7 oscillations in vitro, whereas CLOCK/BMAL1-driven arrest of Hes7 oscillations persisted in gastruloids despite ectopic Hes7 rescue. These findings identify 11{beta}-HSD2 as a developmental buffer and support the physiological importance of the temporal architecture controlling the timing of circadian clock development.

developmental biology↗

bioRxiv2021

Non-coding enhancer RNA regulates NPAS4 in the mPFC to control chronic stress-induced anhedonia-like behavior

Chronic stress can produce reward system deficits (i.e. anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain unclear. We show here that the neuronal activity-regulated transcription factor, NPAS4, in the mPFC is regulated by chronic social defeat stress (CSDS), and its required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation. Interestingly, NPAS4 is not required for CSDS-induced social avoidance or anxiety-like behavior. We also find that mPFC NPAS4 is required for CSDS-induced reduction of pyramidal cell dendritic spine density, revealing a relationship between mPFC dendritic spine changes and anhedonia-like behavior, but not social avoidance behavior. Finally, transcriptomic analysis from the mPFC revealed that NPAS4 influences expression of numerous genes linked to glutamatergic synapses and ribosomal function, as well as many dysregulated genes observed in common neuropsychiatric disorders, including depression. Together our findings reveal an essential role for the activity-regulated transcription factor, NPAS4, in chronic stress-induced mPFC hypofunction and anhedonia.

neuroscience↗

bioRxiv2020

CLOCK/BMAL1 interferes with segmentation clock oscillation in mouse embryonic organoids

In mammals, circadian clocks are strictly suppressed during early embryonic stages as well as pluripotent stem cells, by the lack of CLOCK/BMAL1 mediated circadian feedback loops. During ontogenesis, the innate circadian clocks emerge gradually at a late developmental stage, then, with which the circadian temporal order is invested in each cell level throughout a body. Meanwhile, in the early developmental stage, a segmented body plan is essential for an intact developmental process and somitogenesis is controlled by another cell-autonomous oscillator, the segmentation clock, in the posterior presomitic mesoderm (PSM). In the present study, focusing upon the interaction between circadian key components and the segmentation clock, we investigated the effect of the CLOCK/BMAL1 on the segmentation clock Hes7 oscillation, revealing that the expression of functional CLOCK/BMAL1 severely interferes with the ultradian rhythm of segmentation clock in induced PSM and gastruloids. RNA sequencing analysis showed that the premature expression of CLOCK/BMAL1 affects the Hes7 transcription and its regulatory pathways. These results suggest that the suppression of CLOCK/BMAL1-mediated transcriptional regulation during the somitogenesis may be inevitable for intact mammalian development.

developmental biology↗

bioRxiv2020

Natural Antisense Transcript of Period2, Per2AS, regulates the amplitude of the mouse circadian clock

Circadian transcriptome studies identified a novel transcript at the Period2 (Per2) locus, which we named Per2AS. Per2AS is a long non-coding RNA transcribed from the antisense strand of Per2, and is expressed rhythmically and anti-phasic to Per2 mRNA. Previously, we mathematically tested the hypothesis that Per2AS and Per2 mutually inhibit each others expression by forming a double negative feedback loop, and found that Per2AS expands the oscillatory domain. In this study, we have experimentally tested this prediction by perturbing the expression of Per2AS in mouse fibroblasts. We found that Per2AS represses Per2 pre-transcriptionally in cis and regulates the amplitude of the circadian clock, but not period or phase. Unexpectedly, we also found that Per2 positively regulates Per2AS post-transcriptionally, indicating that Per2AS and Per2 form a single negative feedback loop. Because knock-down of Per2 does not recapitulate the phenotypes of Per2AS perturbation and Per2AS also activates Bmal1 in trans, we propose that Per2AS regulates the amplitude of the circadian clock without producing a protein by rewiring the molecular clock circuit.

molecular biology↗