Uterine Deletion of Bmal1 Impairs Placental Vascularization and Induces Intrauterine Fetal Death in Mice

Abstract

Recently, it was demonstrated that the expression of BMAL1 was decreased in the endometrium of women suffering from recurrent spontaneous abortion. To investigate the pathological roles of uterine clock genes during pregnancy, we produced conditional deletion of uterine Bmal1 (cKO) mice and found that cKO mice could receive embryo implantation but not sustain pregnancy. Gene ontology analysis of microarray suggested that uterine NK (uNK) cell function was suppressed in cKO mice. Histological examination revealed the poor formation of maternal vascular spaces in the placenta. In contrast to WT mice, uNK cells in the spongiotrophoblast layer, where maternal uNK cells are directly in contact with fetal trophoblast, hardly expressed an immunosuppressive NK marker, CD161, in cKO mice. By progesterone supplementation, pregnancy could be sustained until the end of pregnancy in some cKO mice. Although this treatment did not improve the structural abnormalities of the placenta, it recruited CD161-positive NK cells into the spongiotrophoblast layer in cKO mice. These findings indicate that the uterine clock system may be critical for pregnancy maintenance after embryo implantation.

The Circadian Clock, Nutritional Signals and Reproduction: A Close Relationship

“…Recently, we generated mice with a conditional deletion (cKO) of uterine Bmal1 to examine the pathogenic functions of the uterine clock genes during pregnancy [ 75 ]. We found that cKO mice could achieve embryo implantation but could not maintain pregnancy.…”

Dietary Habit-Induced Gynecologic Disorders in Young Female Students – Lessons from Rodent Experiments

“…Based on this background, to investigate the pathological roles of uterine clock genes during pregnancy, we produced conditional deletion of uterine Bmal1 (cKO) mice [16] using Bmal1-loxP [38] and progesterone receptor-cre mice as reported previously [39,40]. As a result, cKO mice could receive embryo implantation, but not sustain the pregnancy.…”

“…Furthermore, Daikoku et al created mice deficient in the uterus-specific clock gene Bmal1 and observed that the fetuses died before delivery, indicating that abnormal uterine clock function cannot maintain fetal development. The cause of this phenomenon was elucidated to be abnormal placentation accompanied by a failure in the construction of maternal blood vessels, indicating the possibility that reproductive and perinatal diseases are induced by abnormal uterine clock [16].…”

Reproductive Immunology and Pregnancy 2.0

“…As the core circadian locomotor output cycle kaput (CLOCK) gene, BMAL1 is rhythmically expressed in many tissues, including uterine and placental tissues, and is responsible for controlling the circadian expression of numerous target genes involved in many physiological processes [11,12]. It has been suggested that reduced endometrial BMAL1 expression is associated with an increased risk of spontaneous recurrent miscarriages in humans [13,14]. Decidual cells deficient in BMAL1 expression showed inhibitory effects on trophoblast invasion into uterine spiral arteries [15].…”

“…These findings at the molecular level should prompt a reassessment of the systemic consequences of disruption of the biological clock, especially with regard to fertility [16]. Moreover, the insufficient invasion of trophoblast cells, which is the main factor involved in the development of pre-eclampsia, is caused by the impaired activity of natural killer (NK) cells [14,15]. Therefore, if the cytolytic activity in NK cells required for trophoblast invasion follows a daily rhythm, it may be disrupted as a result of decreased BMAL1 expression [17].…”