Biology subjects

Robker, R.

Publications and source records attributed to Robker, R..

4 recordsLinked to original sources

bioRxiv2025

A network of steroid receptor transcription factors regulates ovarian chromatin remodelling in the transition to ovulation

Steroid receptors are transcription factors activated by progesterone (PGR), androgen (AR) and glucocorticoid (GR), with shared canonical DNA binding sequence. In the ovary, PGR is the key determinant of ovulation while AR and GR play important roles in growing follicles. However, the mechanism that defines the unique physiological roles of these conserved receptors, and whether their functions overlap remains elusive. We investigated the relationship between AR, GR and PGR during folliculogenesis and ovulation. In response to ovulatory hormones, PGR and GR jointly gained binding to novel chromatin sites and had a substantial effect on periovulatory gene regulation, whereas AR-chromatin interactions were repressed. Two modes of PGR action to drive gene activation were identified. Induction of PGR leads to cooperative PGR/GR recruitment to novel promoters, increased histone acetylation and chromatin accessibility, culminating in transcription activation, with PGR being the key component in the unique ovulatory transcriptional complex. Alternatively, PGR tethered to enhancers interacts with pre-accessible, AR/GR-bound promoters to promote gene activation. Our findings illustrate the multi-faceted ovarian steroid receptor interactions which explain how the progressive change in steroid environments throughout folliculogenesis programs granulosa cells during the transition to ovulation.

genomics↗

bioRxiv2023

N-cadherin mechanosensing in ovarian follicles controls oocyte maturation and ovulation

The cell adhesion molecule N-cadherin (CDH2) is a membrane component of adherens junctions which regulates tissue morphogenesis and architecture. In the follicles of mammalian ovaries, N-cadherin adherens junctions are present between granulosa cells, cumulus cells and at the interface of cumulus cell transzonal projections and the oocyte. We demonstrate a mechanosensory role of N-cadherin integrating tissue structure and hormonal regulation of follicular morphogenic events including expansion of the cumulus oocyte complex (COC) matrix, oocyte maturation and ovulation. Two small molecule N-cadherin antagonists inhibited COC maturation in vitro. Transcriptome profiling revealed that targets of {beta}-catenin and YAP1 pathways were dysregulated by N-cadherin antagonists. In vivo, N-cadherin antagonist significantly reduced ovulation in mice compared to controls (11 vs 26 oocytes/ovary; p=5.8x10-6). Ovarian follicles exhibited structural dysgenesis with granulosa and cumulus cell layers becoming disorganised and the connection between cumulus cells and the oocyte disrupted and the transcriptome again indicated altered mechanical sensing causing dysregulation of the Hippo/YAP and {beta}-catenin pathways and ECM reorganization. Granulosa specific N-cadherin depletion in Cdh2Fl/FL;Amhr2-Cre also showed significantly altered mechanosensitive gene expression and reduced ovulation. Our findings demonstrate a critical role for N-cadherin in ovarian follicular development and ovulation, and the potential to inhibit ovulation through targeting this signalling mechanism.

cell biology↗

bioRxiv2022

Sex-specific transgenerational effects of diet on offspring life history and physiology

Dietary variation in males and females can shape the expression of offspring life histories and physiology. However, the relative contributions of maternal and paternal dietary variation to phenotypic expression of latter generations is currently unknown. We provided male and female Drosophila melanogaster diets differing in sucrose concentration prior to reproduction, and similarly subjected grandoffspring to the same treatments. We then investigated the phenotypic consequences of this dietary variation among grandsons and granddaughters. We demonstrate transgenerational effects of dietary sucrose, mediated through the grandmaternal lineage, which mimic the direct effects of sucrose on lifespan, with opposing patterns across sexes; low sucrose increased female, but decreased male, lifespan. Dietary mismatching of grandoffspring-grandparent diets increased lifespan and reproductive success, and moderated triglyceride levels, of grandoffspring, providing insights into the physiological underpinnings of the complex transgenerational effects on life histories.

evolutionary biology↗

bioRxiv2021

Maternal and paternal sugar consumption interact to modify offspring life history and physiology

Intergenerational effects on offspring phenotypes occur in response to variation in both maternal and paternal nutrition. Because the combined maternal and paternal effects are rarely considered together however, their relative contributions, and the capacity for interactions between parental diets to shape offspring life history and physiology are not understood. To address this, we altered sucrose levels of adult fruit flies (Drosophila melanogaster) prior to mating, across two generations, producing parent-parent and parent-offspring combinations that were either matched or mismatched in dietary sucrose. We then measured lifespan, fecundity, body mass, and triglyceride levels in parents and offspring. We reveal complex non-additive interactions, that involve diets of each parent and offspring to shape offspring phenotypes, but the effects were generally not consistent with an adaptive response to parental diet. Notably, we find that interacting parental flies (sires and dams) lived longer when their sucrose treatments were matched, but they produced shorter-lived offspring.

evolutionary biology↗