Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice

Chihiro Kawaguchi,Atsushi Ichikawa,Shuh Narumiya,Yukio Ago,Yasushi Okuno,Masataka Nakamura,Michiyoshi Hatanaka,Atsushi Kasai,Akemichi Baba,Katsuya Nonomura ,Kazuhiro Takuma,Ai Kuromi ,Soken Tsuchiya,Takahiro Nakazawa ,Hiroyuki Hirai,Atsuko Hayata‐Takano ,Reiko Nakamura ,Kazuhiro Nagata ,Yui Yamano,Yoshihiro Urade,Yusuke Shintani,Yukihiko Sugimoto,Norihito Shintani,Hitoshi Hashimoto

doi:10.1038/s42003-020-01281-w

Abstract

We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAP-deficient mice. L-PGDS-deficient mice also showed impaired light-induced phase advance, but normal phase delay and nonvisual light responses. Then, we examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471. These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling.

Highlights

We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift
The analysis revealed that an increase in lipocalin-type prostaglandin (PG) D synthase (L-PGDS)[13,14] expression in response to light stimulation in the late subjective night was not observed in PACAP−/− mice
We found that the individual intensity of L-Pgds signals in each cell was significantly increased by light at circadian time (CT) 21 in the suprachiasmatic nucleus (SCN) in wild-type mice (Fig. 2e), suggesting that the increased L-Pgds levels (Fig. 1c) are likely attributable to the increased individual intensity of L-Pgds signals in each cell in the SCN

Summary

Introduction

We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAPdeficient mice. We examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/ CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471 These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling. L-PGDS and DP2/CRTH2-deficient mice showed impaired phase advance under low intensity light

Methods

Results

Conclusion