A new role for muscle segment homeobox genes in mammalian embryonic diapause

Abstract

Mammalian embryonic diapause is a phenomenon defined by the temporary arrest in blastocyst growth and metabolic activity within the uterus which synchronously becomes quiescent to blastocyst activation and implantation. This reproductive strategy temporally uncouples conception from parturition until environmental or maternal conditions are favourable for the survival of the mother and newborn. The underlying molecular mechanism by which the uterus and embryo temporarily achieve quiescence, maintain blastocyst survival and then resume blastocyst activation with subsequent implantation remains unknown. Here, we show that uterine expression of Msx1 or Msx2, members of an ancient, highly conserved homeobox gene family, persists in three unrelated mammalian species during diapause, followed by rapid downregulation with blastocyst activation and implantation. Mice with uterine inactivation of Msx1 and Msx2 fail to achieve diapause and reactivation. Remarkably, the North American mink and Australian tammar wallaby share similar expression patterns of MSX1 or MSX2 as in mice—it persists during diapause and is rapidly downregulated upon blastocyst activation and implantation. Evidence from mouse studies suggests that the effects of Msx genes in diapause are mediated through Wnt5a, a known transcriptional target of uterine Msx. These studies provide strong evidence that the Msx gene family constitutes a common conserved molecular mediator in the uterus during embryonic diapause to improve female reproductive fitness.

Embryo-endometrial interactions during early development after embryonic diapause in the marsupial tammar wallaby

“…In the mouse without diapause, expression is transient at early day 4. In contrast, during diapause, Msx1 is highly expressed, and in mice with conditional uterine inactivation of Msx1 and Msx2 there is reduced blastocyst recovery and survival (Cha et al, 2013). These mice also fail to achieve true delay, suggesting that the entry into diapause is under maternal control.…”

“…These mice also fail to achieve true delay, suggesting that the entry into diapause is under maternal control. Oestrogen and progesterone do not directly induce Msx1 but in mice, the effects of Msx genes in diapause are mediated through Wnt5a, a known transcriptional target of uterine Msx (Cha et al, 2013, Nallasamy et al, 2012. Interestingly, Msx1 expression persists in Lif --/ -mice but LIF injection induces implantation and downregulation of Msx1 expression (Cha et al, 2013; also see below).…”

“…Oestrogen and progesterone do not directly induce Msx1 but in mice, the effects of Msx genes in diapause are mediated through Wnt5a, a known transcriptional target of uterine Msx (Cha et al, 2013, Nallasamy et al, 2012. Interestingly, Msx1 expression persists in Lif --/ -mice but LIF injection induces implantation and downregulation of Msx1 expression (Cha et al, 2013; also see below). Loss of Msx1/Msx2 expression correlates with altered uterine luminal/epithelial cell polarity and affects E-cadherin/b-catenin complex formation through the control of Wnt5a expression (Daikoku et al, 2011).…”

“…It is also virtually undetectable on the day before birth and day of birth, but a few days later MSX2 is highly expressed by d4 post-partum and remains high during diapause. After reactivation it decreases progressively up to day 5 RPY (Cha et al, 2013). It is interesting that this basic mechanism controlling embryonic diapause has been conserved between mammals of different orders that have been separated for around 160 million years (Luo et al, 2011) (Fig.…”

Embryonic diapause: development on hold

“…This concept is It was later shown that an ovarian surge of estradiol secretion during late morning of the fourth day following mating is essential to induction of implantation (McCormack and Greenwald, 1974). Much of what we know about rodent implantation can be attributed to use of an experimentally induced diapause model, the ovariectomized, progesterone-treated mouse or rat, in which implantation can be predictably induced by a single administration of estrogen (Cha et al, 2013).…”