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Reproductionreview REPRODUCTIONREVIEW Forkhead transcription factors in ovarian function Nina Henriette Uhlenhaut and Mathias Treier Max Delbru¨ck Center for Molecular Medicine, Robert Ro¨ssle Straße 10, 13125 Berlin-Buch, Germany Correspondence should be addressed to N H Uhlenhaut; Email: [email protected] Abstract Since the discovery of the conserved forkhead (Fkh) DNA binding domain more than 20 years ago, members of the Fkh or forkhead box (FOX) family of transcription factors have been shown to act as important regulators of numerous developmental and homeostatic processes. The human genome contains 44 Fkh genes, several of which have recently been reported to be essential for female fertility. In this review, we highlight the roles of specific FOX proteins in ovarian folliculogenesis and present our current understanding of their molecular function. In particular, we describe what we have learned from loss-of-function studies using mouse models as well as human genetics and illustrate how different stages of folliculogenesis, both in oocytes and in somatic granulosa and theca cells, are regulated by FOXC1, FOXL2, and FOXO subfamily members. Reproduction (2011) 142 489–495 Introduction stages of folliculogenesis. This transition is marked by oocyte growth and proliferation of the adjacent granu- Female fertility depends on a delicate balance of losa cells that become cuboidal. Antral follicles are hormonal stimuli and cellular interactions, which formed when fluid-filled spaces develop between the ultimately enable conception and a successful preg- multi-layered granulosa cells. During preantral to antral nancy. Current estimates state that 10–15% of couples transition, the oocyte resumes meiosis, and after worldwide remain childless due to infertility, with stimulation by pituitary gonadotropins, FSH, and LH, genetic etiology making up a significant proportion the mature oocyte is expelled from the follicle and moves (Matzuk & Lamb 2002). Research using genetic linkage into the oviduct as an unfertilized egg. Concurrently, the analysis or genome-wide association studies as well as remaining granulosa cells undergo luteinization to form genetically modified mouse models is uncovering a an endocrine gland, the corpus luteum, which secretes plethora of novel candidate genes for fertility disorders progesterone to prepare the uterus for implantation and is leading to a better understanding of female (Matzuk & Lamb 2002, Matzuk et al. 2002). reproductive function (Matzuk & Lamb 2008). In addi- It is important to note that the size of the primordial tion to hormones and their receptors as well as signaling follicle pool formed perinatally and the rate of follicular molecules, transcription factors have emerged as power- depletion after birth determine the duration of female ful regulators of ovarian function. It is becoming evident fertility (Erickson 2001). Research performed during that loss of forkhead (Fkh) factors is detrimental to recent years is starting to provide insight into the nature female fertility, which is the subject of this review (Choi of the molecular communication that leads to the & Rajkovic 2006, Richards & Pangas 2010). selective periodic activation and maturation of a subset of primordial follicles (see below). Mammalian folliculogenesis Mature follicles of the mammalian ovary consist of a single oocyte encased by several layers of somatic The Fkh family of transcription factors granulosa cells and a large, fluid-filled cavity (the The forkhead box (FOX) family of transcription factors is antrum). Around birth, the primordial follicle pool is named after the ectopic head structures observed in the established when oocytes are surrounded by a single mutants of the Drosophila gene Fkh, which became the squamous layer of granulosa cells. This finite nongrow- family’s founding member (Weigel et al. 1989, Weigel & ing population, containing oocytes arrested in meiosis, Ja¨ckle 1990). In humans (and in mice), the Fkh family has represents the reproductive potential of the female. On been extended to include 44 members that share a follicular activation, primary follicles are recruited from common DNA binding domain of up to 110 amino the primordial pool and thus committed to subsequent acids. This helix-turn-helix structure consists of three q 2011 Society for Reproduction and Fertility DOI: 10.1530/REP-11-0092 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/27/2021 12:23:23AM via free access 490 N H Uhlenhaut and M Treier a-helices, three b-sheets, and two ‘wing’ regions flanking In the following paragraphs, we will focus on those the third b-sheet and resembling a butterfly, hence the mammalian Fkh family members that have been alternative name ‘winged helix’. Most FOX proteins bind associated with development of the female gonads and to DNA as monomers (Lehmann et al. 2003). ovarian folliculogenesis to date. Outside of the conserved Fkh domain, there is little protein sequence similarity between different clades of the family, which include transcriptional activators as FOXC1 well as repressors (see Fig. 1). The FOX family is highly In addition to its role in eye development, one study conserved throughout evolution, and their nomenclature has implicated FOXC1 in early ovarian function. Foxc1 is based on a phylogenetic classification of Fkh domain homozygous mutant mice display impaired migration protein sequences from more than ten species (FOXA of primordial germ cells (PGCs) to the gonadal anlage. through FOXS; Hannenhalli & Kaestner 2009). In those animals, PGCs are initially specified correctly in Fkh factors have been shown to influence a diverse the absence of FOXC1, but do not migrate efficiently to range of biological processes. For instance, FOX genes the genital ridges, with many PGCs remaining trapped are necessary for the establishment of the body axis, in the hindgut, and the developing gonad being smaller for the development of cell types from all three germ and disorganized. To circumvent the neonatal lethality layers, for metabolic and immunoregulatory processes, of the knockout mice, the authors performed trans- as well as cell cycle control and cellular survival. plantation experiments and found that in wild-type adult Oncogenic fusion proteins with members of the FOXO hosts, Foxc1 mutant follicles do not develop beyond subfamily have been implicated in rhabdomyosarcoma preantral stages (Mattiske et al. 2006). This report and leukemia. Furthermore, the expression levels of indicates that FOXC1 may be required for maturation several Fkh genes have been correlated with various of follicles beyond the early antral stage, but its potential types of cancer. Currently, 11 different human develop- target genes and regulatory mechanism remain to be mental disorders have been associated with mutations elucidated. Despite a substantial amount of data on in FOX genes, with an interesting prevalence of eye FOXC1 mutations causing Axenfeld–Rieger malfor- abnormalities. Namely, mutations in FOXC1, FOXC2, mations and glaucoma observed in human patients, FOXE3, and FOXL2 lead to ocular phenotypes in mice there are no data available at present on human allelic and humans (Lehmann et al. 2003, Hannenhalli & variants of FOXC1 with regard to female fertility (Tumer Kaestner 2009). & Bach-Holm 2009). FOXL2 and blepharophimosis/ptosis/epicanthus FOXO3 FOXK2 inversus syndrome FOXK1 FOXO1 FOXO6 FOXO4 Mutations in the human FOXL2 gene are the cause of FOXF2 FOXH1 FOXF1 the autosomal dominant blepharophimosis/ptosis/ FOXJ3 epicanthus inversus syndrome (BPES, MIM *605597; FOXQ1 FOXJ2 FOXD4 Crisponi et al. 2001). The characteristic dysplasia of FOXD3 FOXD2 FOXJ1 FOXN3 the eyelids observed in BPES patients can be associated FOXD1 FOXN2 with premature ovarian failure (POF; BPES type I) or not FOXE3 (BPES type II). POF is defined as the onset of menopause FOXE1 FOXM1 before the age of 40 years. There is a certain variance in FOXS1 FOXN1 the clinical spectrum associated with FOXL2 mutations, FOXC2 FOXN4 FOXC1 with infertility ranging from primary amenorrhea to irregular menses followed by POF and ovarian appear- FOXB2 ance varying from ostensibly normal to streak gonads FOXB1 FOXP1 FOXA3 FOXL2 (De Baere et al. 2001). Depending on the type FOXP4 FOXP2 FOXI3 FOXL1 FOXP3 and position of the mutation within the FOXL2 coding FOXA2 FOXI2 FOXG1 FOXA1 FOXI1 sequence, a putative genotype–phenotype correlation FOXR1 could be derived: mutations closer toward the FOXR2 N-terminus, leading to the production of a truncated Figure 1 The forkhead transcription factor family. Phylogenetic tree FOXL2 protein, most likely lead to loss of function and of all known human forkhead family members, based on similarity cause both ovarian failure and eyelid abnormalities of protein sequences. The nomenclature of subfamilies is derived from (BPES type I), whereas extensions such as frameshifts or a phylogenetic classification of forkhead domain protein sequences from more than ten species (including invertebrates). Alignment and duplications represent hypomorphic alleles and dendrogram of human FOX protein sequences was performed using result in BPES type II (De Baere et al. 2003, 2009, CLUSTALW. Beysen et al. 2009). Reproduction (2011) 142 489–495 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/27/2021 12:23:23AM via free access FOX transcription factors in the ovary 491 C-terminal of the DNA binding domain, the FOXL2 activation and premature depletion
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