Ovarian follicles are the fundamental function units in which oocytes are protected and grow. Whereas the formation of primordial follicles is the first stage of folliculogenesis and the foundation for their further development, the primordial follicle pool established at birth represents the total germ cell population available to a female during her entire reproductive life. In mouse embryo, germ cells originate from primordial germ cells around 6.5 days post coitum (dpc) [1], which migrate to the urogenital ridge on 10.5dpc and are referred to oogonia once they colonize the ovary [2, 3]. By 13.5dpc, oogonia proliferate through mitotic division to form the cluster, refer as cysts or nests [4], then enter meiosis initiated by retinoic acid signaling and differentiate into oocytes [5]. The oocytes proceed through prophase I of meiosis progressing through a series of sub-phases starting with pre-meiotic interphase and then moving through leptotene, zygotene, pachytene, and eventually arresting at the diplotene stage [2]. Just before or after birth, oocytes undergo a wave of apoptosis, and the cysts are broken down by a massive loss of oocytes [6, 7]. While dormant oocytes are surrounded by pre-granulosa cells to form the primordial follicles [2, 8]. The population of primordial follicles is established perinatally, serves as a finite oocyte pool [9], and only a small proportion of primordial follicles is activated concurrently, with activation resulting in follicular growth and the serial development of primary, secondary, preantral and antral follicles to support a continuous ovulatory cycle, which are dependent on pituitary gonadotrophins during the female reproductive lifespan [2, 6].
However, the activation and dormancy of oocytes undergo dynamic alterations in gene expressions, which are regulated by numbers of factors, including FOXO3 [10, 11], PTEN [12, 13], PI3K/AKT/mTOR signaling [8] and casein kinase I (CK1) family [14]. In addition, the formation of primordial follicles is dependent on the communication between germ cells and somatic cells established as early as 13.5dpc [6]. Together, the oocytes and granulosa cells embark on a complex and coordinated program of oocytes differentiation, formation of primordial follicles and their development. Although there are numbers of reports about the molecular events affecting primordial follicle formation and initiating follicle growth, the functions and mechanisms of CK1 family regulating oogenesis and/or folliculogenesis remain elusive.
CK1 is a family of serine/threonine protein kinases [15, 16], which widely exists in eukaryotes, from yeast to humans [17, 18]. Molecular genetic studies have shown that there exist at least seven genetically distinct isoforms of CK1 termed α, β, γ1, γ2, γ3, δ and ε, and they are greater than 50% identical to one another [15, 16, 19]. Their functions include roles in circadian rhythms [20], cellular transformation, mammary carcinogenesis [21], nucleo-cytoplasmic shuttling of transcription factors [22], DNA repair [23] and mRNA metabolism [14]. In addition, it is reported that CK1α, encoded by Csnk1a1 gene, is co-localized with condensed chromosomes during mouse oocyte meiosis and early embryo development [14, 24, 25]. CK1α is thus required for chromosome alignment and segregation during oocyte meiotic maturation by affecting the phosphorylation of Rec8 [26, 27]. These functional studies of CK1α on oocyte meiosis and maturation were performed by using in vitro CK1α knock down, CK1α RNAi, microinjection of CK1α antibodies, or by using CK1α inhibitors [25, 28]. However, another study shows that CK1, including CK1α, may not be essential for mammalian oocyte meiotic progression [28]. Collectively, although numerous studies have demonstrated the potential roles of CK1 in cell division, the roles of CK1α in the developmental ovary and oocyte maturation is still controversial.
To determine the role of CK1α in oogeneosis and/or folliculogenesis, an oocyte-specific CK1α conditional knockout (cKO) mouse was established in this study. The results firstly demonstrate that oocyte CK1α deletion impairs the meiotic progression of oocyte and formation of primordial follicles, which subsequently cause oocyte loss and mouse infertility by enhancing cell apoptosis and autophagy.