Knockdown of FOXO3 induces primordial oocyte activation in pigs

Journal of Reproduction and Development

et al. 2011

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Abstract. The objective of the present study was to elucidate the involvement of FOXO3 in the activation of bovine primordial follicles. In immunohistochemistry, FOXO3 was detected in all of the oocytes in primordial and primary follicles. The FOXO3 decreased after treatment with FOXO3 small interfering RNAs (siRNAs). Ovarian tissues containing dominantly primordial follicles were treated with FOXO3 siRNAs and then xenografted to severe combined immune deficiency (SCID) mice. Two months after xenografting, some primordial follicles developed to the secondary and tertiary stages, and the total percentage of these developing follicles (secondary and tertiary follicles: 18 ± 7%) was higher than in the control grafts treated with control siRNA (7 ± 1%). It is thought that bovine primordial follicle activation is regulated by the FOXO3-dependent mechanism and that knockdown of FOXO3 induces the release of primordial follicles from FOXO3 suppression, initiating their growth. Key words: Bovine, FOXO3, Primordial follicle, Severe combined immune deficiency (SCID) mouse, Xenografting (J. Reprod. Dev. 57: [475][476][477][478][479][480] 2011) he mammalian ovary contains a large number of primordial follicles. The primordial follicle consists of a nongrowing oocyte arrested at the diplotene stage of meiosis I and a surrounding single layer of flat-shaped granulosa cells. Ruminant primordial follicles are formed during fetal life [1], which is earlier than in rodents, whose primordial follicles are formed around the time of birth [2,3]. Flat-shaped granulosa cells change their morphology into a cuboidal shape [4] to form primary follicles, and oocytes start to grow. This change is called primordial follicle activation. During the female reproductive life, only small proportions of oocytes in primordial follicles enter the growth phase, while the others remain quiescent [5]. The mechanism of primordial follicle activation is not well understood.Bovine primordial follicles from fetal ovaries initiate growth within 2 days of culture [6]. Development of fetal bovine follicles to the antral stage (tertiary follicle) 15 weeks after xenografting to nude mice has been reported [7]. However, it has also been reported that bovine primordial follicles from adult animals do not develop 4-6 weeks after xenografting to severe combined immune deficiency (SCID) mice [8]. We recently showed that primordial follicles from 15-day-old piglets developed to the tertiary stage 2 months after xenografting, whereas those from 6-month-old animals did not develop [9], suggesting that neonatal pig ovaries contained a mixed population of activated and quiescent primordial follicles, while primordial follicle activation was perhaps negatively regulated by some factors in adult animals, since the follicles had the ability to initiate development 4-6 months after xenografting [10].Castrillon et al. [11] reported that global activation of primordial follicles occurred in Foxo3 -/-mice. FOXO3 is one of the forkhead transcription factors, which are charact...

mentioning

confidence: 96%

FOXO3 Knockdown Accelerates Development of Bovine Primordial Follicles

Bao

Hayakawa

Journal of Reproduction and Development

et al. 2011

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“…Our recent report revealed that FOXO3 regulates the dormancy and later activation of primordial oocytes in adult ovaries [28]. In prepubertal pigs, FOXO3 was expressed in the nuclei of almost all primordial oocytes, and in infant pigs, a number of primordial oocytes did not exhibit FOXO3.…”

Section: Inhibitory Factors Of Primordial Oocytesmentioning

confidence: 95%

“…FOXO3 expression has been observed in the nuclei of mouse and rat oocytes [86], and Foxo3 -/-mice show global follicular activation, which leads to the early depletion of ovarian follicles [87]. These studies suggest that Foxo3 inhibits primordial oocyte activation in newborn rodents.Our recent report revealed that FOXO3 regulates the dormancy and later activation of primordial oocytes in adult ovaries [28]. In prepubertal pigs, FOXO3 was expressed in the nuclei of almost all primordial oocytes, and in infant pigs, a number of primordial oocytes did not exhibit FOXO3.…”

mentioning

confidence: 95%

“…After the same duration of xenografting, primordial follicles from neonatal (10-to 20-day-old) piglets developed to the antral stage along with enlargement of oocytes [24]. At 4 months after xenografting, a few primordial follicles started to develop, and at 6 months, the follicles developed to various stages, including antral follicles, along with oocyte growth [28]. With respect to growth initiation, the ability of primordial oocytes in adult ovaries might be different from that in fetal or neonatal females.…”

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confidence: 99%

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Growth of Primordial Oocytes in Neonatal and Adult Mammals

Miyano

2010

J. Reprod. Dev.

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Abstract. Mammalian ovaries are endowed with a huge number of small oocytes (primordial oocytes) in primordial follicles. A small number of primordial oocytes start to grow, while others remain quiescent. Little is known about the mechanism regulating the activation of primordial oocytes. Recently, we found that primordial follicles in mature cows and prepubertal pigs took longer to initiate growth in xenografts compared with those in neonatal animals. We think that primordial oocytes in adult mammals are different from those in neonatal mammals. In this review, we summarize the results regarding the activation of primordial oocytes in neonatal and adult ovaries of different species and propose a model in which ovaries of neonatal mammals contain a mixed population of both quiescent and activated primordial oocytes, while almost all primordial oocytes are quiescent in adult females. The dormancy of primordial oocytes may be required to reserve the non-growing oocyte pool for the long reproductive life in mammals. FOXO3 is considered one of the molecules responsible for the dormancy of primordial oocytes in adult ovaries. These quiescent primordial oocytes are activated, perhaps by certain mechanisms involving the interaction between stimulatory and inhibitory factors, to enter the growth phase. Key words: Adult, Neonatal, Oocyte growth, Ovary, Primordial follicle (J. Reprod. Dev. 56: [559][560][561][562][563][564][565][566] 2010) n fetal ovaries, germ cells known as oogonia proliferate mitotically and become oocytes that enter the meiotic cell cycle, and the oocytes then become arrested at prophase I. At around birth in rodents and during mid-gestation in humans and pigs, oocytes (15-20 μm in diameter in rodents and 30 μm in diameter in humans and pigs) are enclosed by a single layer of flattened follicular epithelial cells (granulosa cells; Fig. 1). This unit consisting of an oocyte and granulosa cells is called the primordial follicle. The oocytes in primordial follicles are called "primordial oocytes" [1]. After formation of primordial follicles, some of the primordial oocytes begin to grow, although most spend months or years in the quiescent state. Activation of primordial oocytes causes the transformation of their surrounding granulosa cells to a cuboidal shape [2]. The follicles at this stage are called primary follicles that contain growing oocytes. The granulosa cells proliferate and become multilayered to form secondary follicles. As follicles develop through the primary, secondary and tertiary (antral) stages, they gain successive layers of granulosa cells, oocytes increase in size towards 70-75 μm in rodents and 120-125 μm in humans, cows and pigs and theca cell layers surround the follicles. Finally, a large fluid-filled antral cavity (follicular antrum) is formed, and the follicle is called a tertiary or antral follicle.The time point at which first activation of primordial oocytes occurs depends on the species. In mice, growth of a portion of oocytes begins within several days after birth [3,4]...

“…In the xenotransplantation experiment, primordial oocytes from prepubertal pigs took a longer time to initiate the growth compared with those from neonatal pigs. However, after transient knockdown of FOXO3 by the small interfering RNA (siRNA) interference, a proportion of primordial oocytes from prepubertal pigs became activated and entered the growth phase in the xenografts [9].…”

Section: Foxo3mentioning

confidence: 99%

Foxo3 negatively regulates the activation of mouse primordial oocytes

Kashiwagi

Reprod Medicine & Biology

Miyano

2012

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Purpose The objective of this study is to know the role of Foxo3, a forkhead transcription factor, in the growth initiation of primordial oocytes in neonatal mice. Methods We studied the expression of Foxo3 in 0-, 1-, 2-, 7-and 21-day-old mouse ovaries by immunohistochemistry. Ovaries from 1-day-old mice were treated with Foxo3 siRNAs (small interfering RNAs) and subsequently organcultured for 6 days, and the oocyte growth was examined histologically. Results Expression of Foxo3 was low in newborn mouse ovaries. In 1-day-old ovaries, Foxo3 was expressed in the nuclei of 20 ± 7 % primordial oocytes. The percentage of Foxo3-positive primordial oocytes was increased to 48 ± 8, 37 ± 2 and 47 ± 4 in 2-, 7-and 21-day-old mice, respectively. After treatment of ovaries with Foxo3 siRNAs, higher proportion of oocytes entered the growth phase in cultured ovaries than that in control. Conclusions These results suggest that Foxo3 negatively regulates the growth initiation of primordial oocytes and knockdown of Foxo3 leads primordial oocytes to the growth phase in vitro.