Diﬀerentiation (2005) 73:1–17 r International Society of Diﬀerentiation 2005 R E V IE W Jia L. Song . Gary M. Wessel How to make an egg: transcriptional regulation in oocytes Received October 14, 2004; accepted October 17, 2004 Abstract The oocyte is a highly differentiated cell. It makes organelles specialized to its unique functions and progresses through a series of developmental stages to acquire a fertilization competent phenotype. This review will integrate the biology of the oocyte with what is known about oocyte-specific gene regulation and transcription factors involved in oocyte development. We propose that oogenesis is reliant on a dynamic gene regulatory network that includes oocyte-specific transcriptional regulators. Key words oogenesis primordial germ cells oocytes gonadal development transcriptional regulation Introduction An oocyte must undergo several developmental transitions during which it acquires a specialized extracellular matrix and synthesizes a unique set of proteins in order to become a fertilizable egg. The making of an egg is dictated by networks of oocyte-specific gene expression patterns that are at least in part regulated by transcriptional mechanisms discussed in this review. Little is known about the transcriptional proﬁle within an oocyte and how oocyte-specific genes are regulated throughout the lifetime of an egg. Development of the egg begins with the formation of primordial germ cells (PGCs) in the embryo and is followed by oogonial proliferation by mitosis, and initiation of meiosis I as primary oocytes. Oocytes may be . ) Jia L. Song Gary M. Wessel (* Department of Molecular and Cell Biology and Biochemistry Brown University 69 Brown Street Box G-J4 Providence, RI 02912 USA Tel: 11 401 863 1051 Fax: 11 401 863 1182 E-mail: [email protected] U.S. Copyright Clearance Center Code Statement: arrested in the ﬁrst prophase of meiosis from 12–50 years in humans, up to 3 years in frogs, and up to a year for most echinoderms. In response to various signals from gonadal somatic cells, the primary oocytes then grow, differentiate, and meiotically mature. Throughout the development of the oocyte, or oogenesis, the oocyte must make all the necessary maternal factors in preparation for fertilization. A hallmark of the oocyte across many species is its high level of transcription, reﬂecting the importance of maternal mRNAs and proteins that are crucial for supporting not only the growth of the oocyte, but the newly fertilized zygote as well (Smith and Richter, 1985; Davidson, 1986; Wassarman and Kinloch, 1992). The complexity and careful regulation of the transcriptional activity of the oocyte dictate its ultimate acquisition of developmental competence. This review will combine data and models from diverse oocyte types to emphasize our current knowledge of oocyte transcriptional regulation and transcription factors that play a role in the regulation of oocyte development. Biology of the oocyte An oocyte is a specialized cell whose differentiated phenotype supports fertilization and early development. In addition to having vast numbers of organelles typical to a eukaryotic cell such as the endoplasmic reticulum, mitochondria, and the Golgi apparatus, it also possesses organelles unique to the oocyte functions. These include annulate lamellae, cortical granules, and yolk granules (Lash and Whittaker, 1974; Wessel et al., 2001). Each of these structures is made largely by the oocyte and relies on oocyte-specific gene activity at high levels. In addition, all animal eggs are surrounded by one or more extracellular coats made specifically by the oocyte (Dumont and Brummett, 1985). The extracellular matrix of the oocyte plays a crucial role in both fertilization and early development. Many eggs of both vertebrate and invertebrate animals, such 0301–4681/2005/7301–1 $ 15.00/0 2 Fig. 1 Egg morphologies differ greatly throughout phylogeny, yet each egg constructs an elaborate extracellular matrix involved in both the fertilization process and in early development. Shown are eggs representative of the bilaterian evolutionary branches, deuterostomes, ecdysozoans, and lophotrochozoans, and include the following: a sea urchin (Lytechinus variegatus; echinoderm) egg in the process of fertilization (A) DIC image, see lifting fertilization envelope on the left) and (B) an SEM view of the vitelline layer (Chandler and Heuser, 1980); (C) a pool of frog (Xenopus laevis, amphibian) eggs, along side a quick-freeze, deep etched view of the surface of a frog egg (D) showing the plasma membrane, the overlying vitelline layer, and a cortical granule immediately below the plasma membrane (Larabell and Chandler, 1988); (E) a newly fer- tilized ﬁsh embryo (Danio rerio), with its expanded chorion (Kimmel et al., 1995) and (F) an inset of a SEM view of a fractured chorion at the sperm-entry point, the micropyle (Wolenski and Hart, 1987); (G) a hamster egg (Mesocricetus auratus) embedded in its zona pellucida and cumulus mass shown by brightﬁeld (Gilbert, 2000) and (H) an SEM view of the zona pellucida following removal of the cumulus cells (http://www.bioone.org/bio one/?request=get-document&issn=0006-3363&volume=063&issue= 05&page=1437#ﬁgures); (I) the chorion of a ﬂy egg (Drosophila melanogaster) shown by SEM (http://www.molbio.princeton.edu/ facility/confocal/SEM/IMAGELIST1.html); and (J) the surface of a shrimp egg, shown by SEM, with sperm attached to its vitelline layer apparent in the inset (K). as frogs and sea urchins, are surrounded by an outer jelly coat and an inner vitelline envelope (Fig. 1) (Wessel et al., 2001). In contrast, ﬂies and ﬁsh are surrounded by a tough chorion layer, whereas all mammalian eggs are surrounded by a thick coat, called the zona pellucida (ZP). The molecular composition of each of these extracellular coats appears distinct from each other; yet, they are functionally analogous. In mammals and ﬁsh, an extensive oocyte extracellular matrix is synthesized during oogenesis prior to fertilization, and the contents of the cortical granule, membrane-bound, stimulus-dependent secretory vesicles, further modify the extracellular matrix at fertilization (Fig. 1) (Wessel et al., 2001). At the other extreme are frog and sea urchin oocytes that have a minimal extracellular matrix but massive secretions of cortical contents transform the extracellular matrix following fertilization. The extracellular matrix of the egg contains specialized components that ensure proper binding and activation of the sperm. In sea urchins, a protective, physical barrier for the developing oocyte is composed of the egg jelly synthesized by somatic cells and contains sperm chemoattractants and peptides (such as speract and resact) that activate the sperm (Gilbert, 2000). Apposed to the plasma membrane of the egg is the vitelline layer, which consists of a network of glycoproteins (Dumont and Brummett, 1985). The main function of the vitelline layer prior to fertilization is for sperm attachment but is sufﬁciently porous to allow the transfer of macromolecules into the growing oocyte. The vitelline 3 Fig. 2 Cortical granules of two species of sea urchins shown by transmission electron microscopy. (A) Stongylocentrotus purpuratus cortical granules apposed to the plasma membrane of the egg contain a spiral lamellar, primo, substructure adjacent to a homogenous electron lucent region. The 15 nm gold particles are attached to antibodies against SFE9, a structural protein destined for the fertilization envelope, showing that proteins are specific to the cortical granules and to only the spiral region. (B) Cortical granules of Arbacia punctulata showing a distinct, stellate substructure, even though the contents appear conserved between different sea urchin species (Wong and Wessel, 2004). Scale bar 5 0.5 mm. layer also serves as a scaffold for the attachment of proteins released by the cortical granules at fertilization in the formation of the fertilization envelope (reviewed in Wessel et al., 2001). Molecules in the cortical granules are specific to the oocyte and serve their function only during fertilization (Fig. 2). So far, of the 12 cortical granule proteins characterized in the sea urchin, all except two are the result of genes whose activities are unique to the oocytes (Wessel et al., 2001; Wong and Wessel, 2004). The analogous extracellular structure in mammals, the ZP, is formed during oogenesis and increases in thickness as the oocyte grows. During fertilization, sperm must bind to and penetrate the ZP in order to fuse with the egg plasma membrane (reviewed in Wassarman et al., 2004). Following fertilization, the cortical granule contents released by the oocyte modify the ZP to block additional sperm penetration. In addition, the ZP prevents the developing mammalian blastocyst from adhering to the oviduct wall as it travels to the uterus. The blastocyst embryo hatches from the ZP by using a trypsin-like protease, strypsin, thus enabling implantation (Perona and Wassarman, 1986). Another specialized family of proteins whose presence is dependent upon oocyte-specific gene activity is the proteins associated with yolk acquisition and storage. Yolk proteins are the nutritional source for all nonplacental embryos and depending on the animal and the protein, they can either be synthesized in various organs of the adult and imported into the oocyte, or be syn- thesized by the oocyte directly (reviewed in Brooks and Wessel, 2003). In egg-laying species, oocytes contain low-density lipoprotein receptors on their surface that bind to yolk components such as vitellogenin and other ligands and selectively transport them into oocytes via receptor-mediated endocytosis (Schneider, 1996). Vitellogenin receptors have been identiﬁed in a wide range of animals including insects, frogs, ﬁsh, and birds (Schneider, 1996; Sappington and Raikhel, 1998). In sea urchin oocytes, in addition to the proteins responsible for the uptake of exogenously synthesized MYP (Major Yolk Protein), the oocyte also synthesizes YP30 (Yolk Platelet Protein of 30 KDa) (Wessel et al., 2000b; Brooks and Wessel, 2003). YP30 is synthesized exclusively by sea urchin oocytes, is packaged selectively into yolk platelets, and is hypothesized to function in the packaging and storing of other yolk proteins during oognesis. In other animals, including mollusks, polchaetes, and crustaceans, ultrastructural analyses suggest that yolk is also synthesized by the oocyte (Eckelbarger, 1979; Zerbib, 1980; Kress, 1982; reviewed in Brooks and Wessel, 2003). In order for the oocyte to carry out its specialized functions, it likely requires a unique repertoire of transcriptional strategies. Following the transition from an oogonia, the developing oocyte generally increases its transcriptional activity, resulting in a stockpile of mRNA and proteins that can be utilized quickly following fertilization and embryogenesis (Smith and Richter, 1985; Davidson, 1986; Wassarman and Kinloch, 1992). The accumulation 4 of mRNAs by oocytes during its growth phase is crucial to later development, and oocytes that have not completed their growth phase fail to develop properly as embryos (Fair et al., 2004; reviewed in Fair, 2003). Some gene products are only synthesized and utilized during the life of the oocyte. For example, the RNA transcripts of the ZP genes, which encode gene products that make up the mammalian egg coat, increase markedly during mouse oogenesis and then decrease to undetectable levels prior to ovulation (Roller et al., 1989; Epifano et al., 1995). Similarly, in sea urchins, oocytespecific genes involved in modiﬁcation of the extracellular matrix analogous to the ZP, such as Soft Fertilization Envelope genes, SFE1, SFE9, and Ovoperoxidase (OPO), also increase in abundance during oogenesis until oocyte maturation (Laidlaw and Wessel, 1994; LaFleur et al., 1998; Wessel et al., 2000a). Each of these transcripts is then selectively degraded, and their expression is repressed, so that these transcripts are not detectable following oocyte maturation. Ovoperoxidase is an enzyme that catalyzes the covalent tyrosine cross-linking of the structural proteins of the envelope, SFE1 and SFE9. These structural proteins modify the extracellular environment of the oocyte to prevent polyspermy and are constructed promptly after fertilization (LaFleur et al., 1998; Wessel et al., 2000a). The transcript dynamics of YP30 is similar to that of the SFE and OPO in that its mRNA is most abundant in developing oocytes and is no longer detectable upon oocyte maturation (Wessel et al., 2000b). What makes the oocyte unique begins with the proper transcription of oocyte-specific genes. Numerous studies have focused on the general biology of oocyte development and meiotic regulation, but little is known of the transcriptional regulatory mechanisms of oocytes. Is the transcriptional proﬁle within the oocyte uniform throughout oogenesis or do transitions occur indicative of a progressive transcriptional network? Are oocyte-specific genes regulated by unique sets of regulatory proteins throughout oogenesis or does the cell use master gene regulators? Gametes develop from PGCs Gametes develop from PGCs that are established during early embryogenesis. In the nematode Caenorhabditis elegans, the fruit ﬂy Drosophila melanogaster, and the frog Xenopus laevis, PGCs originate from a morphologically distinct region of the zygote during early embryonic divisions (Fig. 3) (Ikenishi, 1998). In sea urchins and mammals, the PGCs appear to be induced de novo from other cells in the early gastrulating embryo (Lawson and Hage, 1994; Ransick et al., 1996; McLaren, 2003). PGCs have an extragonadal origin and navigate through various tissues to reach the somatic gonad. Overall, the mechanisms of PGC migration are highly conserved in divergent animal classes and involve intrinsic and somatic cues, attraction and repulsion, and amoeboid motility (Matova and Cooley, 2001; McLaren, 2003; Raz, 2003). Several molecules involved in the molecular mechanisms of germline establishment have been localized to PGCs in different animal species. Some of these molecules are conserved germline determinants, such as vasa, tudor, pumilio, nanos, germ cell less, and mago nashi, while others appear species specific, such as oskar in ﬂies and pgl-1 in worms (reviewed in Matova and Cooley, 2001; Extavour and Akam, 2003). Most of these germline factors are involved in translational regulation. Oct-4, however, is a maternally inherited transcription factor that is essential for the maintenance of the mammalian germline (Pesce and Scholer, 2000; Fuhrmann et al., 2001) (discussed below). Oct-4 is postulated to function as a transcriptional activator of genes required in maintaining an undifferentiated totipotent state and may repress the transcription of lineage-specific regulatory genes. Once in the gonad, germ cells begin to actively divide mitotically and become either oogonia or spermatogonia. In many invertebrate and vertebrates, oogonia divide to form clusters of interconnected cells (Pepling et al., 1999; Matova and Cooley, 2001). As the meiotic process is initiated, oogonial germ cells are referred to as primary oocytes. Primary oocytes undergo extreme growth, from 10 mm up to several centimeters, depending on the animal, and this growth involves bidirectional communication between the germ cells and the gonadal somatic cells (De La Fuente and Eppig, 2001; Matzuk et al., 2002). The somatic cells provide nutrients and secrete signals important for the growth of the oocyte. In Drosophila and C. elegans, the oocyte develops in a syncytium (Gibert et al., 1984; reviewed in Matova and Cooley, 2001). In different vertebrates, including zebraﬁsh, Xenopus, chicken, and most mammals, clusters of oogonial cells undergo a growth phase within cysts (Ukeshima and Fujimoto, 1991; Matova and Cooley, 2001; Raz, 2003). The surface membranes of oocytes and their surrounding granulosa cells in mice are connected by gap junctions, which facilitate the transfer of glucose metabolites, amino acids, and nucleotides from the follicular cells to the growing oocytes (Eppig, 1991; Wright et al., 2001). Oocyte-secreted factors play key roles in the development and differentiation of ovarian follicles. Oocytespecific factors that inﬂuence follicular development include proteins of the transforming growth factor b superfamily members, growth differentiation factor (GDF-9), and bone morphogenic protein (BMP-15) (Dong et al., 1996; Yan et al., 2001). Mice lacking GDF-9 are infertile because of a lack of follicular development, and mice lacking BMP-15 have decreased ovulation and fertilization rates (Dong et al., 1996; Yan et al., 2001). The bidirectional communication between 5 A C. elegans P1 egg B 2-cell zygote 16-cell embryo Drosophila egg C P4 cleavage embryo syncytial blastoderm embryo Xenopus blastocoel animal vegetal Egg D Blastula 2-cell embryo Chick E Mouse germinal crescent amniotic cavity primitive streak area pelluoida anterior primitive streak epiblast area opaca Fig. 3 Origin of PGCs. Germ plasm in (A–C) is shown in red; PGCs in all panels are depicted in red as well. (A) Caenorhabditis elegans P granules are distributed throughout the mature egg. They are segregated away from the somatic lineage through a series of unequal divisions that produces the P1 blastomere in the 2-cell embryo and the germline founder, P4, in the 16-cell embryo. (B) Drosophila pole plasm is localized at the posterior end of the mature egg. The early embryo undergoes synchronous nuclear divisions without cytokinesis. Nuclei that arrive at the posterior end of the embryo are the ﬁrst to cellularize, thus forming pole cells that include pole plasm. (C) Xenopus germinal plasm is localized to the vegetal pole of the mature egg. It is partitioned equally between the ﬁrst four blastomeres and ingresses along the cleavage planes. At the blastula stage, germinal plasm is found in about 20 cells that are positioned near the ﬂoor of the blastocoel. (D) Chick PGCs are ﬁrst detected at the blastodisc stage. They are mostly found in a region called the germinal crescent that is positioned anteriorly to the embryo proper. (E) Mouse PGCs can be visualized at around day 7.5 postfertilization. They are found in the area of the epiblast that is proximal to the primitive streak. Modiﬁed from Matova and Cooley (2001). the oocyte and follicle cells involves autocrine, paracrine, and endocrine regulations and ensures their proper differentiation and development. animals contain lampbrush chromosomes, readily observed in the growing oocytes of organisms that produce large eggs. These chromatin loops of transcriptional activity were ﬁrst observed by Flemming (1882) in urodele oocytes and examined in detail by Ruckert (1892) in shark oocytes. In the 1960s, autoradiographic studies carried out with the light microscope showed that intense RNA synthesis occurs throughout the lateral loops of the lampbrush chromosomes (Gall and Callan, 1962; Hill and Macgregor, 1980; Davidson, 1986). In large oocytes that contain excessive pools of maternal RNA, lampbrush chromosomes reﬂect a maximal and continuous ﬂow of transcription products Discovery of transcriptional activity in the oocyte—a historical perspective The study of transcriptional regulation has a deep history in oocytes. Even before the central dogma was posed, structures within the oocyte nucleus were intensively investigated that led to our understanding of transcriptional units. For example, the oocytes of many 6 throughout oogenesis (Smith and Richter, 1985; Davidson, 1986). Lampbrush chromosomes are not a prerequisite for the synthesis and accumulation of maternal message though, because not all oocytes contain these structures (Smith and Richter, 1985; Davidson, 1986). Maternal RNAs were demonstrated in the 1930s and are deﬁned as RNAs synthesized by the oocyte prior to fertilization but utilized in early embryogenesis (reviewed in Davidson, 1986). In many species examined (including echinoderms and amphibians), maternal RNA has high complexity and is sufﬁcient to support all the needed protein biosynthesis required during early development (reviewed in Davidson, 1986). The timing of activation of zygotic genes is species dependent and is highly variable. For example, zygotic gene activation occurs within minutes in sea urchins, at the two-cell stage in mice, four- to eight-cell stage in cows and humans, eight- to 16-cell stage in sheep and rabbits, and not until the mid-blastula transition in amphibians (Schultz and Heyner, 1992). Prior to zygotic gene activation, the zygote is supported by maternal mRNAs transcribed and translated during oogenesis. First example of oocyte-specific gene regulation: oocyte-type rRNA In the early 1960s the bulk of the maternal RNA stored in eggs was known to be rRNA (Davidson, 1986). The store of maternal ribosomes inherited in the egg cytoplasm is sufﬁcient to support protein synthesis immediately following fertilization and in the ﬁrst few stages of embryogenesis. The most thoroughly examined gene regulation in the oocyte is the transcription of 5S RNA genes (reviewed in Smith and Richter, 1985; Wolffe, 1994). Two types of 5S RNA genes exist in the Xenopus oocyte: an ‘‘oocyte type’’ present in about 20,000 copies and a ‘‘somatic type’’ present in about 400 copies per haploid genome (Brown and Sugimoto, 1973; Ford and Southern, 1973; Peterson et al., 1980). The regulation of 5S RNA was initially examined by a cell-free transcription system in which puriﬁed somatic 5S RNA gene was observed to be transcribed in extracts from both oocyte and unfertilized eggs, whereas oocyte 5S RNA gene was only transcribed from the oocyte extract (reviewed in Wormington and Brown, 1983; Smith and Richter, 1985). The transcription of 5S RNA genes requires the general transcription factors TFIIIA, B, and C, and the 5S RNA gene promoter lies within the gene itself (internal control region (ICR)) (Fig. 4) (Wolffe, 1994). The oocyte and somatic 5S RNA genes have a total of 5 bp difference within the ICR, of which 3 bp are located within the TFIIIC-binding site. This sequence variation contributes to the preferential association of TFIIIC to the somatic 5S RNA gene (Fig. 4) (Wolffe, 1988, 1994; Fig. 4 The oocyte and somatic 5S RNA genes and the 5S RNA gene transcription complex. (A) The oocyte (major variant) gene family has a repeating unit of 650–850 bp and consists of a gene (open arrow) and a pseudogene (open box) separated by an A1Trich spacer. The somatic gene family has a repeating unit of 880 bp consisting of a gene (open arrow) and a G1C-rich spacer. (B, C) Differential transcription factor association with oocyte and somatic 5S RNA genes inﬂuences transcription during development. (B) TFIIIA and TFIIIC interactions with oocyte and somatic 5S RNA genes. TFIIIA forms a specific complex with both oocyte and somatic 5S RNA genes. Both of these complexes are unstable (Kd 5 10–9 M). TFIIIC recognizes TFIIIA bound to both 5S RNA genes, however, because of sequence differences at one of the key contacts made by the protein (vertical arrows), TFIIIC does not stabilize the TFIIIA/oocyte 5S DNA complex. Thus TFIIIA remains in free equilibrium with factors in solution (open arrowheads). In contrast, TFIIIC rapidly stabilizes TFIIIA association with the somatic 5S RNA gene. (C) During oogenesis the excess of TFIIIA (molecules per gene) is high, as embryogenesis proceeds past the stage at which transcription is activated (the mid-blastula transition, MBT) towards neurulation, this excess declines rapidly. The transcriptional activity of oocyte and somatic 5S RNA genes at these different stages is indicated. From Wolffe (1994). Keller et al., 1990, 1992). TFIIIA forms a specific but unstable complex with the 5S gene. TFIIIC recognizes the TFIIIA/5S DNA complex and recruits TFIIIB, which is then recognized by RNA polymerase III (Bieker et al., 1985; Setzer and Brown, 1985; Kassavetis et al., 1990). During oogenesis, the somatic and oocyte 5S RNA genes are transcribed with nearly the same efﬁciency when TFIIIA is in excess (Wolffe, 1994). So where is the transcriptional switch that distinguishes somatic and oocyte 5S gene activities? Recent evidence suggests that phosphorylation of Xenopus TFIIIA by casein kinase II allows the factor to act as an activator of the somatic 5S RNA and as a repressor of the oocytetype 5S RNA upon oocyte maturation (Ghose et al., 7 2004). Phosphorylated TFIIIA binds to the promoters of both the somatic and oocyte-type 5S RNA genes, but it represses the transcription of the oocyte-type 5S RNA selectively, possibly by interfering with protein–protein interactions necessary for oocyte-type transcription (Ghose et al., 2004). An important mediator of 5S RNA gene transcription also involves changes in chromatin structure (reviewed in Panetta et al., 1998; Crane-Robinson, 1999). The expression of linker histone protein (H1) is developmentally regulated; in Xenopus it is translated during early embryogenesis but not in oocytes (Wolffe, 1994; Panetta et al., 1998; Crane-Robinson, 1999). In the presence of the histone H1, a stable nucleosome is positioned on the oocyte 5S RNA gene that prevents binding of TFIIIA, whereas on the somatic 5S RNA gene, essential promoter elements remain accessible to TFIIIA (Bouvet et al., 1994; Panetta et al., 1998; Sera and Wolffe, 1998). Thus, this oocytespecific transcriptional mechanism does not rely on oocyte-specific factors. Rather, differential regulation of shared or common factors results in this oocytespecific activity. Oct-4: one of the early master gene regulators? One of the few transcription factors known to be involved in the self-renewal of embryonic stem (ES) cells is Oct-4. This factor belongs to the Pit-Oct-Unc (POU) family of transcription factors containing both a homeobox sequence and a POU-specific domain (Verrijzer et al., 1992). It binds to an octamer motif and interacts with DNA through a helix–turn–helix domain. Orthologs of Oct-4 in mice, bovines, and humans share highly conserved genomic organization and regulatory regions (Nordhoﬀ et al., 2001; Kurosaka et al., 2004). Oct-4 is selectively expressed in totipotent embryonic and germ cells (Pesce et al., 1998b; Pesce and Scholer, 2000). At the blastocyst stage in mammals, the outer layer of the blastocyst is the trophectoderm and the cells inside are the inner cell mass (ICM). The ICM is composed of pluripotent stem cells that give rise to all cell types of the embryo, including the germ cell lineage. Oct-4 mRNA is present uniformly throughout the morula stage and becomes restricted to the ICM of the blastocyst (Fig. 5A). After embryo implantation in the mouse, Oct-4 transcription is restricted to the epiblast and ES cells (Yeom et al., 1996; Pesce et al., 1998a). Oct-4 transcription is then progressively down-regulated during gastrulation and eventually conﬁned to the PGCs (reviewed in Pesce and Scholer, 2000). This function is presumably involved in retention of germline stem cell fates. The candidate target genes that are up-regulated by Oct-4 during mouse implantation include Fibroblast Growth Factor-4 (FGF-4) and Osteopontin (OPN) (Guo et al., 2002). FGF-4 is thought to stimulate ICM growth or maintenance and is involved in the establishment of the primitive endoderm in vivo (Wilder et al., 1997), and OPN is an endodermal-specific, extracellular phosphoprotein that mediates adhesion by interacting with integrins (Guo et al., 2002). In contrast, both a and b forms of human chorionic gonadotropin are downregulated by Oct-4 (Liu et al., 1997). Chorionic gonadotropin prevents the regression of the corpus luteum during early pregnancy, and is expressed by trophectodermal cells. Therefore, Oct-4 functions as both a transcriptional activator and repressor of its different target genes in ensuring the end result of potency in ES cells. Given its critical role in maintaining pluripotency of the germ cells, Oct-4 is of special interest in our understanding of the continuity of the germline. The Oct-4 gene is driven by a TATA-less minimal promoter and at least two enhancer elements (Okazawa et al., 1991; Yeom et al., 1996). The minimal promoter contains a GC box with putative-binding sites for Sp1 and Sp3 transcription factors and a hormone-responsive element (HRE) (Sylvester and Scholer, 1994). The HRE contains binding sites for the steroid–thyroid receptor family and orphan nuclear receptor superfamily, specifically COUP-TFI, ARP-1, EAR-2, and GCNF, which downregulate Oct-4 transcription (Okazawa et al., 1991; Pikarsky et al., 1994; Sylvester and Scholer, 1994; Ben-Shushan et al., 1995; Schoorlemmer et al., 1995; Fuhrmann et al., 2001). The distal enhancer is necessary for Oct-4 transcription in the morula, ICM, and PGCs, while the proximal enhancer (PE) activates Oct-4 in the epiblast (Yeom et al., 1996). The PE element is not only a transcriptional enhancer but is also a cis-demodiﬁcation element that demethylates Oct-4 during specific stages of embryogenesis, spermatogenesis, and oogenesis, when other genes undergo de novo methylation (Ben-Shushan et al., 1993; Gidekel and Bergman, 2002; Pan et al., 2002). During gonadal development, transcription of Oct-4 in mouse and human germ cells remains high until the onset of meiosis (Pesce and Scholer, 2000; Kurosaka et al., 2004; Rajpert-De Meyts et al., 2004). Oct-4 transcription in oogonia and spermatogonia is down-regulated at specific stages of oogenesis and spermatogenesis (Pesce et al., 1998a; Kurosaka et al., 2004; Rajpert-De Meyts et al., 2004). In the spermatocyte lineage of the adult mouse, Oct-4 protein is expressed in undifferentiated A spermatogonia and is down-regulated as the germ cells begin spermatogenic maturation (Pesce et al., 1998a). Oct-4 expression in human testes is similar to ﬁndings in mice, except that Oct-4 protein is undetectable from adult spermatogonia (Rajpert-De Meyts et al., 2004). In mouse oocytes, Oct-4 mRNA and 8 Oct-4 upregulation A Zygote 4-cell Cleavage 8-cell Compacted morula Epiblast ICM B 12.5 13.5 14.5 15.5 16.5 17.5 18.5 1 dpp 2 dpp 3 dpp Oct-4 expression proliferation arrest at diplotene meiotic entry zygotene/pachytene birth Fig. 5 (A) Oct-4 expression in preimplantation and early postimplantation development in mouse. Present as a maternal transcript in the zygote, Oct-4 is expressed at low levels until the eight-cell stage, when the zygotic Oct-4 gene is turned on. Until the compaction of the morula, Oct-4 is expressed equally in all blastomeres to be eventually conﬁned in the inner cell mass, and after implantation, in the epiblast. From Pesce et al. (1998a). (B) In female germ cells, Oct-4 expression is down-regulated coincident with the entry into the prophase of the ﬁrst meiotic division. At 15.5 dpc, correspondent to the zygotene/pachytene stage of meiotic prophase I, Oct-4 is absent in oocytes. It is not re-expressed until birth, when diplotene-arrested oocytes start expressing it de novo. Modiﬁed from Pesce et al. (1998a). protein are down-regulated when the oocyte enters prophase of the ﬁrst meiotic division and are re-expressed near oocyte maturation (Fig. 5B) (Pesce et al., 1998a, 1998b). Similarly, in fetal human ovaries, Oct-4 is present in primordial oogonia during fetal development and is down-regulated in oocytes that entered the ﬁrst meiotic prophase; some Oct-4 molecules might be transported to the cytoplasm at the onsest of meiosis, but the biological significance of this phenomenon is unknown (Rajpert-De Meyts et al., 2004). Oct-4 may play a role in the growth or acquisition of meiotic competence of oocytes, and/or it may be involved in transcriptional repression of oocyte-specific genes, since Oct-4 is transcribed minimally during a time when the oocyte is undergoing an overall increase in transcriptional activity, and Oct-4 is transcribed abundantly at oocyte maturation when transcriptional activity in the oocyte decreases dramatically (Pesce et al., 1998b). Recently, the expression of Oct-4 has been examined in human testes and ovaries during fetal development, and its aberrant expression may contribute to disorders in sex differentiation and malignant gonadal tumors in humans, highlighting its critical role in gonadal development (Looijenga et al., 2003; Rajpert-De Meyts et al., 2004). The germ cell-specific transcription factor FIGa regulates oocyte-specific genes FIGa is a germ cell-specific transcription factor that regulates the coordinated transcription of the three ZP glycoproteins, ZP1, ZP2, and ZP3, and may regulate additional pathways critical for ovarian development (Fig. 6) (Liang et al., 1997; Dean, 2002). The ZP proteins form an extracellular matrix that surrounds the growing mammalian oocyte and are critical for sperm activation and for the block to polyspermy. Mouse ZP3 has been shown to contain the primary species-specific sperm receptor of the oocyte, binding sperm via O-linked oligosaccharide chains and inducing the sperm 9 Fig. 6 Model summarizing the expression and exchange of ALF and TFIIA during oogenesis in Xenopus laevis. The model suggests the exclusive use of the germ and somatic transcription factors ALF and TFIIA in germline and somatic tissues. An earlier transition from TFIIA to ALF is predicted at or about the time cells commit to meiosis. The model also illustrates a transition from ALF to TFIIA that occurs during maturation, fertilization, and early embryogenesis up to the mid-blastula transition (MBT). Modiﬁed from Han et al. (2003). acrosome reaction (Bleil and Wassarman, 1990; Cheng et al., 1994, 1998; reviewed in Wassarman, 1988; Dean, 2002, 2004; Wassarman et al., 2004). Mouse ZP2 acts as a secondary sperm receptor and plays a role in the prevention of polyspermy, while ZP1 cross-links the other two ZP proteins (Wassarman et al., 2004). Targeted mutagenesis in mice demonstrated that either ZP2 or ZP3 homozygous nulls result in infertility in females but not in males (Rankin et al., 2001). Mice lacking ZP1 have abnormal zona matrices that are more porous than normal and result in early embryonic loss (Rankin et al., 1999). In most vertebrates analyzed, including mammals, Xenopus, and several ﬁsh, ZP genes are present, active, and contribute to the egg’s extracellular matrix, even though the extracellular matrix may vary structurally. The transcription of ZP glycoproteins is temporally and spatially restricted to oocytes in most vertebrates (Wassarman, 1990; Epifano et al., 1995; Kubo et al., 1997; Wang and Gong, 1999; Zeng and Gong, 2002). However, in some organisms the ZP proteins are synthesized elsewhere. For example, the chick ZP3 is synthesized by follicle cells surrounding the embryo and the ZP1 homolog is transcribed in the liver (Waclawek et al., 1998; Bausek et al., 2000). In some teleost ﬁsh species also, ZP components are transcribed in the liver (Del Giacco et al., 1998). Transcription of ZP genes in some organisms provides a paradigm for examining mechanisms and evolution of oocyte-specific gene transcription. In the mouse, transcription of ZP proteins is coordinately regulated by FIGa (Liang et al., 1997). FIGa heterodimerizes with a ubiquitous b-helix–loop–helix (bHLH) E12 protein and regulates the mouse ZP genes by binding to a canonical E-Box (CANNTG) approximately 200 bp upstream of the transcription start sites of ZP genes (Millar et al., 1991; Epifano et al., 1995; Liang et al., 1997). Functional homologs of FIGa have been identiﬁed in humans, zebraﬁsh, and medaka (Liang et al., 1997; Kanamori, 2000; Huntriss et al., 2002; Onichtchouk et al., 2003; Bayne et al., 2004), and FIGa homologs bind interchangeably to the zebraﬁsh ZPC and human ZP2 promoters, respectively (Onichtchouk et al., 2003; Bayne et al., 2004). FIGa is expressed in both the testis and ovary, but is expressed most abundantly in the ovary of mouse (Liang et al., 1997). FIGa is ﬁrst detected in oocytes at E13.5 in mice and its transcript persists in oocytes into adulthood (Liang et al., 1997). Mice lacking FIGa are unable to express ZP genes or form primordial follicles, resulting in massive depletion of oocytes and sterility (Liang et al., 1997). However, cotransfection of FIGa and E12 in 10T1/2 embryonic ﬁbroblasts is not sufﬁcient to activate endogenous zona gene transcription, indicating that FIGa plays an important regulatory role in conjunction with other, yet unknown factors (Liang et al., 1997). Recently, the human FIGa homolog has also been found to heterodimerize with E12 protein and bind to the E-Box of the human ZP2 promoter, suggesting a conserved mechanism in controlling ZP genes and primordial follicle formation in the human as in the mice ovary (Bayne et al., 2004). NoBox regulates oocyte-specific gene transcription The homeobox gene, Nobox (newborn ovary homeobox-encoding gene), was ﬁrst identiﬁed by in silico subtraction of a murine newborn ovary cDNA library 10 against the entire collection of mouse expression sequence tags (Suzumori et al., 2002). Nobox transcripts are detected in both mouse male and female gonads by reverse transcription-polymerase chain reaction (RTPCR), and in situ hybridization results indicated that Nobox transcripts are present in murine oocytes from primordial through antral follicles but not in somatically derived granulosa cells, theca cells, and corpora lutea (Suzumori et al., 2002). NoBox protein localizes to the nuclei of germ cells and primordial follicles in the mouse ovary (Rajkovic et al., 2004). Disruption of 90% of the Nobox coding region including the homeodomain in the mouse resulted in infertile female mice, while males were unaffected (Rajkovic et al., 2004). Histomorphometric analyses indicated that the relative numbers of oocytes, germ cells, and primordial follicles were similar in Nobox1/ and Nobox / newborn ovaries (Rajkovic et al., 2004). However, by day 14 the Nobox / ovaries revealed a great loss of oocytes, indicating that the majority of oocyte and follicle growth beyond the primordial follicle stage was disrupted by the absence of Nobox (Rajkovic et al., 2004). Further examination indicated that in Nobox / ovaries, transcripts of genes that are preferentially transcribed in the oocyte, including Mos, Oct-4, Rfpl4, Fgf8, Zar1, Dnmtlo, Gdf9, Bmp15, and H1oo, were downregulated (Rajkovic et al., 2004). The transcription of Nobox precedes the transcription of these genes, suggesting that Nobox may directly or indirectly regulate these genes that are important for oocyte and early embryo development (Rajkovic et al., 2004). A portion of the human Nobox homolog was also identiﬁed, but its function has not been examined (Suzumori et al., 2002). Germ cell-specific general transcription factor ALF The differentiation and restoration of totipotency of germ cells involve tightly controlled gene expression patterns. A set of general transcription factors are necessary for an accurate initiation of transcription. ALF (TFIIAt) is a counterpart of the large a/b subunit of the general transcription factor TFIIA. ALF interacts with the small TFIIA subunit to form a heterodimeric complex that stabilizes binding of TBP (TATA-binding protein) to core promoter DNA. ALF is transcribed specifically in testis and ovary of Xenopus and mice (Han et al., 2001). It was ﬁrst identiﬁed in male germ cells and is expressed during the pachytene stage of meiotic prophase I in males (Han et al., 2001). In immature Xenopus oocytes, the maternal TFIIAa/b mRNAs are translationally repressed through a conserved 3 0 UTR, and ALF compensates for the maternal storage and inactivation of TFIIa/b mRNAs (Han Fig. 7 Multiple targets for FIGa. FIGa heterodimerizes with a ubiquitous bHLH protein, E12, and binds upstream of one or more genes, the expression of which is required for primordial follicle formation. In addition, FIGa is required for the expression of the three zona pellucida genes (Zp1, Zp2, and Zp3), without which the zona matrix is not formed. The persistence of FIGa in oocytes from embryonic day 13 until the oocytes are fully grown suggests that FIGa may regulate additional genes that are important for normal oogenesis and early development. From Soyal et al. (2000). et al., 2003). When oocytes commit to meiosis, a transition from TFIIAa/b to ALF occurs, and during maturation, fertilization, and early embryogenesis, ALF is inactivated and replaced by somatic TFIIAa/b (Fig. 7) (Han et al., 2003). The transcriptional regulation of ALF in male germ cells is associated with reduced methylation at promoter-proximal CpG dinucleotides, whereas silencing in somatic tissues is associated with increased methylation (Xie et al., 2002). The promoters of mouse and human ALFs contain a short GC-rich region that is active when transfected into COS-7 and 293 cells (Xie et al., 2002). Transgenic mice containing this 133 bp ALF promoter linked to b-galactocidase and GFP reporter genes indicated that this promoter fragment was sufﬁcient to direct specific transcription of ALF in both male and female germ cells (Han et al., 2004). Factors that regulate the differentiated transcription of ALF, however, have not been identiﬁed. The results from Xenopus and mice suggest an evolutionary conserved role for ALF in the germ cell differentiation programs. ALF is one of a few germ cell-specific general transcription factors identiﬁed to date. Similar critical regulators of the gene transcription program directing male gametogenesis in the fruit ﬂy are the Drosohpila testis-specific TAF homologs: the cannonball (homolog of dTAF5), nht (homolog of dTAF4), mia (homolog of dTAF6), sa (homolog of dTAF8), and rye (homolog of dTAF12) (Lin et al., 1996; Hiller et al., 2001, 2004). Mutations in can, nht, sa, and mia all block spermatid differentiaion. ALF may regulate germ cell-specific gene expressions during gametogenesis, since RNA polymerase II does not initiate transcription efﬁciently without general transcription factors, including TFIIA. Examination of the transcriptional regulation of ALF indicates that epigenetic modiﬁcation such as 11 methylation may be an important regulatory mechanism of transcription. Identiﬁcation of germ cell-specific transcription factor ALF and other tissue-specific TAF homologs suggest that the germ cell genome has evolved specialized transcription machinery to ensure the proper activation of genes that are required for germ cell development. that leads to oocyte atresia (Schmidt et al., 2004). Therefore, proper gene expressions in ovarian somatic cells, as exempliﬁed by TAFII105 and FOXL2, affect the growing oocyte and contribute to the proper overall ovarian development. Potential oocyte-specific regulatory factor— Oogenesin Tissue-specific transcription factors important for somatic contribution to oogenesis Ovarian development involves combinatorial factors present in both the oocytes as well as in the somatic ovarian tissues. Transcription factors expressed by the follicular cells in the ovarian tissue are also now known to be important for oogenesis, such as the mouse TAFII105 and FOXL2 factors. TAFII consists of TBPassociated factors that are part of the TFIID general transcription initiation complex. The TFIID complex binds to the core promoters and directs RNA polymerase II to begin transcription. TAFII105 is highly expressed in granulosa cells that surround the maturing mouse oocytes and in the testis (Freiman et al., 2001). Female mice lacking TAFII105 are viable but are sterile, whereas male mice lacking TAFII105 are both viable and fertile (Freiman et al., 2001). TAFII105 controls gene transcription during female gametogenesis as a tissue-specific TFIID subunit. Microarray analysis of heterozygous and knock-out TAFII105 ovaries indicated down-regulation of ovarian-specific genes, including inhibin, aromatase, follistatin, cyclin D2, and 17-bhydroxysteroid dehydrogenase type I (Freiman et al., 2001). These ﬁndings suggest that tissue-specific TFIID-related factors are important in the developmental regulation of gene transcription in gonadal development. Another transcription factor important for ovarian development and function is FOXL2, a winged helix/ forkhead transcription factor that is highly conserved in sequence and pattern of transcription in the early development of the vertebrate female gonad (Cocquet et al., 2003). Mutations in FOXL2 cause the blepharophimosis–ptosis–epicanthus inversus syndrome (BPES), characterized by eyelid malformations and premature ovarian failure in humans (Cocquet et al., 2002, 2003). FOXL2 is expressed in mammalian ovaries early in development, even before the onset of folliculogenesis, and persists until adulthood (Cocquet et al., 2003). The FOXL2 mRNA is detected in both granulosa cells and some oocytes of the fetal and adult mouse ovaries (Loﬄer et al., 2003), although the FOXL2 protein is present only in follicular granulosa cells (Cocquet et al., 2002; Schmidt et al., 2004). Female mice lacking FOXL2 have a depleted pool of primordial follicles because of granulosa cell differentiation failure Most of the known gonadal transcription factors are present in both the testis and ovary, or the so-called ‘‘germline-specific’’ factors. These include FIGa, NoBox, and ALF transcription factors. Recently, two groups have independently identiﬁed an oocyte-specific superfamily of leucine-rich proteins, oogenesin-1–4, by two different methods. Dade et al. (2003) used in silico subtraction of cDNA libraries generated from mouse unfertilized eggs and two-cell zygote to identify oogenesin-1–4. Using differential display comparing RNA transcription of mouse oocytes and preimplantation embryos, Minami et al. (2003) identiﬁed oogenesin-1, which is transcribed in ovaries from 15.5 dpc fetus, coinciding with the start of oogenesis. Oogenesin-1 mRNA and protein are localized in oocytes in primordial, primary, secondary, and antral follicles in the mouse ovary, but in contrast, oogenesin-2–4 mRNAs are detected in oocytes from primary to preovulatory follicles but are not detectable in the primordial follicles (Dade et al., 2003). Low levels of oogenesin-4 transcripts are detected, however, in the testis. The exact roles of oogenesin proteins are not known. Since oogenesin-1 is expressed in the oocytes coincident with the start of primordial follicle formation, oogenesin-1 may be involved in oocyte–somatic cell interactions that lead to folliculogenesis (Minami et al., 2003). Potential regulatory role of Sox in ovarian development The Sox proteins belong to the SRY-type HMG (high mobility group) box superfamily of DNA-binding proteins. They are involved in the regulation of diverse developmental processes such as germ layer formation, organ development, sex determination, and cell type speciﬁcation and are found in all metazoan species (reviewed in Wegner, 1999; Wilson and Koopman, 2002). Sox3 is homologous to the SRY gene (Sex-determining Region of the Y chromosome) and is expressed in the mouse brain and both gonads of the mouse (Collignon et al., 1996; Weiss et al., 2003). In the mouse, Sox3 was determined to be required for gonadal function but not in sex determination in both males and females (Weiss et al., 2003). The mouse Sox3 protein was localized in Sertoli cells of the testis and not in the ovary, although 12 transcripts of mouse Sox3 are detected in oocytes and cumulus cells in the ovary (Weiss et al., 2003). The Sox3 knock-out mice exhibited abnormal growth, tooth development, and altered function of the somatic and germ cells in both sexes (Weiss et al., 2003). Therefore, Sox3 may play a role in gonadal development; however, its target genes have yet to be identiﬁed. Other transcription factors expressed in the gonads An increasing number of transcription factors are found to be expressed in the gonads, but their roles in gonadal development are not known. Northern blot analyses and RT-PCR from adult mouse tissues identiﬁed six Obox (oocyte-specific homeobox) family transcripts that are preferentially expressed in the gonads and that are distinct from the NoBox transcription factors (Rajkovic et al., 2002; Yeh et al., 2002). Obox-1, 2, 3, and 6 mRNA were detected in oocytes, and Obox-4 transcripts were detected in the testes (Rajkovic et al., 2002; Yeh et al., 2002). The protein localization of Obox has not been determined, but they may function either in transcriptional activation of the oocyte genome within the growing follicle, and/or they may be maternal factors that play a role in early embryogenesis. Several groups have examined the transcription and function of homeotic genes in mouse, human, and bovine oocytes and preimplantation stage embyros (Verlinsky et al., 1995; Kuliev et al., 1996; Adjaye and Monk, 2000; Ponsuksili et al., 2001; Villaescusa et al., 2004). In vertebrates, HOX homeobox-containing genes are arranged on four separate chromosomal clusters, A, B, C, and D (reviewed in Gehring et al., 1994). Previous studies using RT-PCR detected HOXA4, HOXA7, HOXB4, HOXB5, HOXD8, and HOXD1 in human oocytes and cleaving embryos (Verlinsky et al., 1995; Kuliev et al., 1996). In addition, the ubiquitously expressed POU family member Oct1, and HEX (Homeotic gene Expressed in the Hematopoiesis) were detected in cDNA libraries derived from human unfertilized oocytes and early embryos (Adjaye and Monk, 2000). In bovine oocytes, HOXA3 and HOXD1 mRNA were detected, with HOXD1 also present in the four-cell stage bovine embryo (Ponsuksili et al., 2001). A similar study was conducted to identify HOX genes expressed in the mouse ovary resulting in the identiﬁcation of HOXA5, HOXA9, HOXB6, HOXB7, HOXC6, and HOXC8 and HOX co-factors PREP and PBX (Villaescusa et al., 2004). The role of HOX transcription factors in mammalian oocytes and early embryonic stages remains to be elucidated. Summary The diverse families of transcription factors discussed in this review include regulatory proteins that are expressed predominantly in oocytes, proteins that are enriched in the gonads, and proteins that are present in oocytes, gonads, and early embryos (Table 1). A survey of existing studies on transcription factors that Table 1 Summary of transcription factors involved in gonadal development RNA expression Protein localization Oocytes Sperm Somatic ovary Somatic testis Oocytes Sperm Somatic ovary Somatic testis Oct-4 111 111 111 111 FIGa 111 N/D 11 111 N/D N/D NoBox 111 N/D 1 111 N/D N/D ALF TAFII105 FOXL2 111 1 111 N/D 1 111 111 1 1 111 N/D 111 N/D N/D N/D 111 N/D N/D Oogenesin-1–3 111 1112 N/D 2 N/D Oogenesin-4 mSox3 Obox 1, 2, 3, 6 111 1 11 N/D 11 11 11 N/D N/D N/D N/D N/D N/D N/D 1 N/D Obox 4 N/D 11 N/D N/D N/D N/D 1 Not distinguished between sperm and somatic testis. Oogenesin 1 only. , not detected; N/D, not determined. 2 Kurosaka et al. (2004), Pesce et al. (1998a, 1998b) Liang et al. (1997), Soyal et al. (2000) Rajkovic et al. (2004), Suzumori et al. (2002) Han et al. (2003, 2004) Freiman et al. (2001) Cocquet et al. (2002, 2003), Loﬄer et al. (2003), Schmidt et al. (2004) Dade et al. (2003), Minami et al. (2003) Dade et al. (2003) Weiss et al. (2003) Rajkovic et al. (2002), Yeh et al. (2002) Rajkovic et al. (2002) 13 4 Oct- gonadal ridge: PGCs develop into oogonia GDF-9 BMP-15 TF 1, 2, 3 e.g. vasa nanos germ-cell-less -4 Oct oogonial proliferation early embryo: PGC specification input signals TF A, B, C oogonia transition to primary oocytes input signals Figα Nobox oocyte growth and development target genes for differentiation YP30 ZP1, 2, 3 SFE 1, 9, Opo, Pln, Rdv mature egg Fig. 8 Model of a putative transcriptional network during the life cycle of oocytes. The process begins with the formation of primordial germs cells, followed by oogonial stem-cell proliferation, entry into meiosis, and oocyte differentiation. Shown are several factors involved in PGC formation (vasa, nanos, germ cell less), in stemcell propagation (Oct-4), in somatic–germ cell interaction (GDF-9, BMP-15) and in oocyte development (FIGa, Nobox). Known oocyte-specific differentiation products are also shown: YP30, ZP1–3, and the cortical granule contents SFE1, 9, ovoperoxidase, proteoliaisin, and rendivin. TF1–3 represent putative pre-meiotic transcription factors that promote mitotic proliferation and inhibit germ cell differentiation. TF A, B, and C are putative post-meitoic transcription factors that promote meiosis, egg maturation, and differentiation. Arrows indicate positive interactions, and bars indicate a repressive function. have a putative role in gonadal development revealed that the majority of regulatory proteins are not restricted to oocytes, but rather, are present elsewhere in the animal. Therefore, the majority of transcriptional mechanisms used in the oocyte will likely center on differences in the regulation of populations of transcription factors that overlap somatic cells of the gonad, embryo, or adult. Studies on gene regulation of 5S RNA, Oct-4, and ALF suggest that chromatin remodeling events such as histone acetylation and DNA methylation are at least part of the molecular mechanism that regulates transcription of these genes. It is likely that the interaction between the chromatin structure and transcription factors together determine the transcriptional activity of specific sets of genes during gametogenesis. The transcriptional regulatory machinery in specifying oocyte development may involve a unique combination of only a few master transcription factors, such as FIGa in regulating oocyte-specific ZP genes in the mouse, utilization of tissue-specific general transcription machinery, interactions with chromatin remodeling and modiﬁcation complexes, and hormonal signals. Concluding remarks and future perspectives Oocytes go through many transitions in their life history. These begin with the speciﬁcation of the PGCs in the embryo, the entry of the germ cells into the gonadal rudiment, the transition of oogonial stem cell to a primary oocyte, and their development into a mature, fertilizable egg. These developmental stages must entail a dynamic network of gene expressions. One model to explain these changes is that this single cell undergoes progressive transitions in transcription factor proﬁles and activities (Fig. 8). While currently we are in a phase of identifying what factors might be present, with dramatic new knowledge in genomics even in oocyte biology, we will quickly confront the problem of how the accumulated factors identiﬁed in oocytes interact to propel the cell forward in a developmental scheme. One would invoke a network of interacting trans-factors with the cis-regulatory elements of the promoters of select transcription factors to regulate the specific expression of these factors. Once a certain level of such a target factor has been achieved, feedback—either directly, or indirectly through additional transcription factors—would up- or down-regulate transcription of the ﬁrst factor. In addition, because of the prolonged periods required for oocyte development, homeostasis of transcription-stable periods would require feedback in the form of a network of positive and negative interactions. While some of these processes are shared with other cells, understanding the oocyte transcriptome would be of great utility to our understanding of germ cells specifically, or stem cells in general. Thus, for both changes in oocyte development and for homeostasis, feedback regulation in the transcriptional proﬁle of oocytes is a necessary process that needs further attention. Acknowledgments We thank Dr. Richard Freiman for his critical reading of this review. We thank Judith Nathanson for ﬁgure construction. This work is supported by grants from the NIH and NSF. 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