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Comment |
As shown in Figure 5A, Ndph and Fzd4 transcripts overlap in the ovary as well as in other mouse tissues, especially the brain and uterus. In the ovary, Ndph message was detected in isolated granulosa cells as well as in the residual tissue remaining after removal of most granulosa cells via needle puncture. Ndph message was expressed in the ovary at multiple stages of follicular development and during ovulation and luteinization, but was not markedly regulated by hormones and was not elevated in luteal tissue (Fig. 5B). Additionally, Ndph mRNA was expressed equally well in Fzd4+/+ and Fzd4−/− mice at Day 5.5 p.c. (Fig. 6). Histological analyses of ovaries from adult 8-wk-old wild-type and null NDP mice revealed an abundance of corpora lutea in each genotype (Fig. 5C) unlike that observed in the 8-wk-old Fzd4−/− mice (Fig. 1); corpora lutea appeared normal in the Ndph−/− mice. That the corpora lutea of the Ndph+/+ as well as the Ndph−/− mice exhibited intense staining for the steroidogenic marker 3βHSD (HSD3β) provided additional evidence that these corpora lutea were functional (Fig. 5D). Thus, despite its expression in the mouse ovary, NDP does not appear to be the key mediator of FZD4 signaling in this tissue, because Ndph−/− mice do not phenocopy the Fzd4−/− mice.
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Mutations |
3 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: Mice Null for Frizzled4 (Fzd4-/-) Are Infertile and Exhibit Impaired Corpora Lutea Formation and FunctionHsieh M, et al .
Previous studies showed that transcripts encoding specific Wnt ligands and Frizzled receptors including Wnt4, Frizzed 1 (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 wildtype litter-mates 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 d1.5 to d7.5 post-coitus (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 pseudoglima homolog; NDPH) 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.
Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - non-ovarian defect
Comment: Fetal loss in homozygous mutant Norrie disease mice: a new role of Norrin in reproduction. Luhmann UF et al. Mutations in the Norrie disease pseudoglioma gene (NDP) are known to cause X-linked recessive Norrie disease. In addition, NDP mutations have been found in other vasoproliferative retinopathies such as familial exudative vitreoretinopathy, retinopathy of prematurity, and Coats disease, suggesting a role for Norrin in vascular development. Here we report that female mice homozygous for the Norrie disease pseudoglioma homolog (Ndph) knockout allele exhibit almost complete infertility, while heterozygous females and hemizygous males are fertile. Histological examinations and RNA in situ hybridization analyses revealed defects in vascular development and decidualization in pregnant Ndph-/- females from embryonic day 7 (E7) onwards, resulting in embryonic loss. Using RT-PCR analyses we also demonstrate, for the first time, the expression of Ndph in mouse uteri and deciduae as well as the expression of NDP in human placenta. Taken together, these data provide strong evidence for Norrin playing an important role in female reproductive tissues.
Species: mouse
Mutation name: None
type: null mutation
fertility: unknown
Comment: Vascular defects and sensorineural deafness in a mouse model of Norrie disease. Rehm HL et al. Norrie disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.
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