The WNT receptors, encoded by the Frizzled genes, are implicated in a variety of cellular processes such as cell fate determination, cell polarity control, and malignant transformation. Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for
Wnt signaling proteins. Chan et al. (1992) isolated from a UMR 106 rat osteosarcoma cell library a cDNA (fz-1) encoding a predicted 641-residue protein (Fz-1) with 46% homology with Drosophila Fz. The fz-1 gene is widely expressed in rat tissues with the highest steady-state levels of mRNA in kidney, liver, heart, uterus, and ovary. fz-1 mRNA levels were greater in neonatal than
in corresponding adult tissues.
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Ovulation
Comment
Expression regulated by
LH
Comment
Richards et al 2002 reported that
the adult ovary of rodents expresses several members of the Wnt/Frizzled signaling pathway in a cell- and
stage- specific manner (M. Hsieh & J.S. Richards, submitted for publication). For example, Wnt4 is expressed in small,
primary follicles in ovaries of immature and adult mice, which suggests that Wnt4 impacts early stages of follicle
growth/formation (M. Hsieh & J.S. Richards, submitted for publication) as well as the initial development of the female
gonad . In addition, Wnt4 is expressed at elevated levels in corpora lutea following the LH surge. At this same time, the
Frizzled 4 receptor is also highly expressed, which suggests that it may be a preferred receptor for Wnt4 in this tissue.
In contrast, the Frizzled 1 receptor is expressed at high levels in granulosa cells of ovulating follicles between
8-12 h after exposure to LH/hCG (M. Hsieh & J.S. Richards, submitted for publication). This spatial and temporal pattern
suggests that Frizzled 1 (and a Wnt ligand yet to be specified) might control unknown events associated with ovulation or
effect certain morphogenic changes that occur during the formation of the corpus luteum.
Ovarian localization
Granulosa, Theca
Comment
Sagara et al. (1998) reported that FZD1 consists of seven transmembrane domains, a cysteine-rich domain in the N-terminal extracellular region, and the C-terminal Ser/Thr-Xxx-Val motif. Relatively large amounts of FZD 1 mRNA, 4.5 kb in size, were detected in adult heart, placenta, lung, kidney, pancreas, prostate, and ovary. Minnie Hsieh et al 2002 reported regulated Expression of Wnts and Frizzleds at Specific
Stages of Follicular Development in the Rodent Ovary.
Wnt ligands and Frizzled (Fz) G protein-coupled receptors impact cell fate, including embryonic development of the ovary.
Because the role of these regulatory molecules during follicular development in the adult is not known, an RT-PCR survey
was done. Wnt-4, Fz-4, and Fz-1 were among the transcripts detected, and each exhibited a specific pattern of expression.
Fz-1 mRNA was low in preovulatory follicles of PMSG-treated mice but was increased within 4-12 h after an ovulatory surge of human CG. By in situ analysis, Fz-1 transcripts increased first in the theca cells and then in the granulosa cells of
ovulating follicles but were low in corpora lutea. In contrast, Wnt-4, a critical factor in early ovarian development, was
expressed in small preantral follicles. In addition, Wnt-4 was detected in preovulatory follicles and exhibited high levels in
corpora lutea. A potential receptor for Wnt-4 in corpora lutea is Fz-4 that was also elevated in this tissue. Although Wnt-4
has been shown to function downstream of the PR in other tissues, Wnt-4 was not altered in follicles of PR-null mice that
fail to ovulate. Rather expression of Fz-1 was lower in ovaries of PR knockout mice, compared with normal littermates.
Thus, specific Wnt/Fz are expressed at distinct stages of follicular development, suggesting multiple functions for this
signaling pathway in the ovary.
Follicle stages
Preovulatory
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: FZD1 Regulates Cumulus Expansion Genes and Is Required for Normal Female Fertility in Mice. Lapointe E et al. WNT4 is required for normal ovarian follicle development and female fertility in mice, but how its signal is transduced remains unknown. Fzd1 encodes a WNT receptor whose expression is markedly induced in both mural granulosa cells and cumulus cells during the preovulatory period, in a manner similar to Wnt4. To study the physiological roles of FZD1 in ovarian physiology and to determine if it serves as receptor for WNT4, Fzd1-null mice were created by gene targeting. Whereas rare Fzd1(-/-) females were sterile due to uterine fibrosis and ovarian tubulostromal hyperplasia, the majority were subfertile, producing 1 less pup per litter on average relative to controls. Unlike WNT4-deficient mice, ovaries from Fzd1(-/-) mice had normal weights, numbers of follicles, steroid hormone production and WNT4 target gene expression levels. Microarray analyses of granulosa cells from periovulatory follicles revealed few genes whose expression was altered in Fzd1(-/-) mice. However, gene expression analyses of cumulus-oocyte complexes (COCs) revealed a blunted response of both oocyte (Zp3, Dppa3, Nlrp5, Bmp15) and cumulus (Btc, Ptgs2, Sema3a, Ptx3, Il6, Nts, Alcam, Cspg2) genes to the ovulatory signal, whereas the expression of these genes was not altered in WNT4-deficient COCs from Wnt4(tm1.1Boer/tm1.1Boer);Tg(CYP19A1-cre)1Jri mice. Despite altered gene expression, cumulus expansion appeared normal in Fzd1(-/-) COCs both in vitro and in vivo. Together, these results indicate that Fzd1 is required for normal female fertility and may act in part to regulate oocyte maturation and cumulus cell function, but is unlikely to function as the sole ovarian WNT4 receptor.