Overexpression of Uromodulin-like1 accelerates follicle depletion and subsequent ovarian degeneration

Abstract

Murine Uromodulin-like 1 (Umodl1) encodes Ca2+-dependent EGF-like membrane-bound proteins. This study presents its novel expression in the immune and female reproductive systems. Upon stimulation by CD3/CD28 antibodies, Umodl1 showed a prompt and robust response in the proliferating CD4+ T cells, suggesting its implication in immune defense against pathogens. In ovary, Umodl1 is regulated by gonadotropins. Mice carrying extra copies of functional Umodl1 were generated by BAC transgenesis. Defects in the female reproductive system became evident from 4 months of age, manifested by reduced or diminished fertility. Histology revealed that the ovaries contained very few discernible follicles in the cortical region, and were devoid of distinguishable corpus lutea (CL). Among the multilayered preantral follicles, elevated apoptosis was observed in both the oocytes and surrounding granulosa cells (GCs). Furthermore, a high level of PPARγ indicated an abnormal adipogenesis in the mutant ovaries, which resulted in the conversion of GCs into adipocytes. By 6 months of age, all mutant mice became anovulatory. Ovarian tissues including CL, follicles of various stages and associated stromal cells were degenerated. Altered expression of AMH, follicle-stimulating hormone and other ovary-specific marker genes such as Gdf-9, Rnf35, NOHLH and Gcx-1 further demonstrated that the molecular properties of the mutant ovaries have been severely disturbed. This work presents a novel animal model for investigating the pathogenesis of premature ovarian failure or early ovarian ageing.

Genomic signatures of extreme body size divergence in baboons

“…Uromodulin-like 1 (UMODL1) helps regulate ovarian development in mice (Wang et al 2012). Regulatory factor X4 (RFX4) is highly expressed in the central nervous system in mice and may mediate ciliogenesis by modulating Sonic hedgehog (Shh) signaling during development (Ashique et al 2009).…”

Unusual tissue distribution of carcinin, an antibacterial crustin, in the crab, Carcinus maenas, reveals its multi-functionality

“…A more recent study has now shown that the protein enhances proliferation of the cancer cells by regulating apoptosis (Chen et al, 2013). Furthermore, in rodents a uromodulin like-1 WFDSC domain-containing protein accelerates age-related ovarian degeneration (Wang et al, 2012). Given that carcinin is not only expressed in regenerating eyestalk, which is well supplied with neural fibres, but is also prominent in ovary and late-stage vitellogenic oocytes, it is not unreasonable to propose that it, and probably…”

Screening of reproduction‐related single‐nucleotide variations from MeDIP‐seq data in sheep

“…Notably, TNIK is proposed to be a biomarker of embryo viability in polycystic ovary syndrome (Huang et al, ), a prediction that matches the differential methylation state of TNIK in women with this disease (Wang et al, ). UMODL1 (SNV of 260,533,475 on chromosome 1) was reported to be expressed in both oocytes and the thymic medulla in mice. Interestingly, mice carrying an extra allele of Umodl1 have drastically reduced litter sizes and increased premature infertility at 6 months of age (Wang et al, ). These data suggest that disruptions to Uromodulin‐like 1 function may accelerate ovarian senescence and, in turn, implies a key role for this gene in fecundity.…”

“…UMODL1 (SNV of 260,533,475 on chromosome 1) was reported to be expressed in both oocytes and the thymic medulla in mice. Interestingly, mice carrying an extra allele of Umodl1 have drastically reduced litter sizes and increased premature infertility at 6 months of age (Wang et al, ). These data suggest that disruptions to Uromodulin‐like 1 function may accelerate ovarian senescence and, in turn, implies a key role for this gene in fecundity.…”