Mice null for Frizzled4 (Fzd4-/-) are infertile and exhibit impaired corpora lutea formation and function.
Previous studies showed that transcripts encoding specific Wnt ligands and Frizzled receptors including Wnt4, Frizzled1 (Fzd1), and Frizzled4 (Fzd4) were expressed in a cell-specific manner in the adult mouse ovary. Overlapping expression of Wnt4 and Fzd4 mRNA in small follicles and corpora lutea led us to hypothesize that the infertility of mice null for Fzd4 (Fzd4-/-) might involve impaired follicular growth or corpus luteum formation. Analyses at defined stages of reproductive function indicate that immature Fzd4-/- mouse ovaries contain follicles at many stages of development and respond to exogenous hormone treatments in a manner similar to their wild-type littermates, indicating that the processes controlling follicular development and follicular cell responses to gonadotropins are intact. Adult Fzd4-/- mice also exhibit normal mating behavior and ovulate, indicating that endocrine events controlling these processes occur. However, Fzd4-/- mice fail to become pregnant and do not produce offspring. Histological and functional analyses of ovaries from timed mating pairs at Days 1.5-7.5 postcoitus (p.c.) indicate that the corpora lutea of the Fzd4-/- mice do not develop normally. Expression of luteal cell-specific mRNAs (Lhcgr, Prlr, Cyp11a1 and Sfrp4) is reduced, luteal cell morphology is altered, and markers of angiogenesis and vascular formation (Efnb1, Efnb2, Ephb4, Vegfa, Vegfc) are low in the Fzd4-/- mice. Although a recently identified, high-affinity FZD4 ligand Norrin (Norrie disease pseudoglioma homolog) is expressed in the ovary, adult Ndph-/- mice contain functional corpora lutea and do not phenocopy Fzd4-/- mice. Thus, Fzd4 appears to impact the formation of the corpus luteum by mechanisms that more closely phenocopy Prlr null mice.
Hsieh
Minnie
M
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Boerboom
Derek
D
Shimada
Masayuki
M
Lo
Yuet
Y
Parlow
Albert F
AF
Luhmann
Ulrich F O
UF
Berger
Wolfgang
W
Richards
JoAnne S
JS
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001808:Blood Vessels / Q000473:pathology; D003338:Corpus Luteum / Q000473:pathology / Q000503:physiopathology*; D010064:Embryo Implantation; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental; D007247:Infertility, Female / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D006080:Ovarian Follicle / Q000502:physiology; D010053:Ovary / Q000098:blood supply / Q000473:pathology; D010060:Ovulation / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D011981:Receptors, Prolactin / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics
D015415:Biomarkers; D005136:Eye Proteins; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011981:Receptors, Prolactin; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C