bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.10.01.322818

Deletion of Gremlin-2 alters estrous cyclicity and disrupts female fertility in mice

Rydze, R. T.·Patton, B.·Torralba, H. S.·Briley, S.·Gipson, G.·James, R.·Rajkovic, A.·Thompson, T. B.·Pangas, S.
View original source ↗Export metadata ↓

Abstract

Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which are known to have key functions during embryogenesis and adult physiology. While BMPs play essential roles in adult female reproductive physiology, the role of the DAN family in ovarian function is less understood. We generated mice null for Grem2 to study its role in female fertility in addition to screening patients with primary ovarian insufficiency for variants in GREM2. Grem2-/- mice are viable and female Grem2-/- mice have diminished fecundity and irregular estrous cycles. This is accompanied by reduced serum levels of anti-Mullerian hormone, a marker of the ovarian reserve, in adult mice. Alterations in ovarian expression of inhibin and activin subunit genes, which are required for regulation of the hypothalamic-pituitary-ovarian (HPO) axis, were identified. While Grem2 mRNA transcript was not detected in the pituitary, Grem2 was expressed in the hypothalami of wild type female mice. Additionally, screening 106 women with primary ovarian insufficiency identified one individual with a heterozygous variant in GREM2 that lies within the predicted BMP-GREM2 interface. In total, these data suggest that Grem2 is necessary for female fecundity by playing a novel role in regulating the HPO axis and possibly contributing to female reproductive disease.

Source connections

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Rydze, R. T., Patton, B., Torralba, H. S., Briley, S., Gipson, G., James, R., Rajkovic, A., Thompson, T. B., Pangas, S.. 2020-10-01. Deletion of Gremlin-2 alters estrous cyclicity and disrupts female fertility in mice. https://doi.org/10.1101/2020.10.01.322818

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Epigenetic Rescue of Disuse Muscle Atrophy by Histone Deacetylase Inhibitor Trichostatin A

Mechanical unloading rapidly induces skeletal muscle atrophy and functional deterioration, yet how the loss of mechanical input influences nuclear architecture, chromatin organization, and associated transcriptional programs remains poorly understood. Here, we investigated whether pharmacological inhibition of histone deacetylases (HDACs) using Trichostatin A (TSA) could attenuate the consequences of continued mechanical unloading in a murine hindlimb suspension model. Following 14 days of unloading, mice exhibited impaired locomotor activity, altered muscle architecture, and widespread transcriptional reprogramming characterized by increased expression of atrophy associated genes, inflammatory mediators, and extracellular matrix remodeling pathways, alongside suppression of mitochondrial metabolic programs. Super resolution imaging further revealed irregular Lamin A/C organization and disruption of discrete H3K9me3 associated heterochromatin foci. Systemic TSA treatment significantly attenuated the decline in locomotor activity, accompanied by trends toward reduced body weight loss, and preservation of muscle morphology. Transcriptomic analysis demonstrated a substantial shift toward the baseline expression profile, with high-dose TSA attenuating FOXO associated catabolic programs, inflammatory, and extracellular matrix-related signatures, while enhancing mitochondrial oxidative phosphorylation pathways. Quantitative gene level and pathway analyses further revealed dose dependent and selective reversal of unloading associated transcriptional changes. Notably, TSA treatment also partially preserved nuclear lamina organization and the focal distribution of H3K9me3 associated heterochromatin. Despite these muscle specific benefits, TSA did not prevent trabecular bone loss over the 14-day unloading period, although several muscle-expressed genes potentially involved in muscle to bone communication were altered by treatment. Together, these findings demonstrate that HDAC inhibition counteracts multiple functional and molecular consequences of skeletal muscle unloading and is associated with partial preservation of nuclear and heterochromatin organization. This study supports a link between mechanical unloading, nuclear architectural remodeling, and HDAC sensitive transcriptional regulation, providing a foundation for epigenetic strategies to counter disuse induced muscle deterioration.

physiology↗
bioRxiv2026

Residual Hearing Loss After Chronic Cochlear Implantation in Guinea Pigs is Primarily Conductive

It is desirous to preserve residual low-frequency hearing in cochlear implant recipients, as dual stimulation using electrical and acoustic signals results in superior speech-in-noise processing and musicality. However, cochlear implant recipients commonly lose their residual acoustic hearing gradually following surgical placement of the array. The governing mechanism is not understood and is likely due to multiple factors including surgical trauma, inflammation, and the foreign body induced immune response to the array, including formation of intracochlear fibrosis. Normal mechanical function of the cochlea is expected to underpin residual hearing but has not been directly studied. This function includes efficient transmission of sound to the cochlea via the middle ear, sound propagation via the basilar membrane travelling wave, mechanical tuning characteristics, and the non-linear cochlear amplification of responses to low-frequency stimulation. Here, we examined these features in cochleae and middle ears of unimplanted, acutely and chronically implanted guinea pigs using our minimally invasive preparation and optical coherence tomography vibrometry. We observed that mechanical tuning and amplification is not significantly altered by either acute or chronic implant. However, the response threshold was raised and proportional to middle ear responses. Additionally, the organ of Corti phase, and its sound intensity dependent changes, are unaltered by CI. Finally, a cluster analysis revealed sensitivity loss in chronically implanted animals is caused by middle ear dysfunction. Hence, in the guinea pig model, the dominant etiology of residual hearing loss is conductive. More research is required to establish whether residual hearing loss in humans similarly shares conductive elements.

physiology↗
bioRxiv2026

Satellite cell glucocorticoid receptor restrains myogenic commitment without mediating the effects of therapeutic glucocorticoids on muscle repair

Glucocorticoids (GCs) exert profound effects on skeletal muscle, but the contribution of satellite cell (SatC) glucocorticoid receptor (GR) signaling to muscle regeneration remains poorly understood. Here, we investigated the role of GR in SatC homeostasis and assessed whether SatC GR mediates the effects of therapeutic GCs on muscle repair. Conditional deletion of GR in SatC reduced the number of PAX7-positive cells during regeneration in young mice, but did not substantially impair muscle repair in either young or aged animals. Transcriptomic and chromatin profiling revealed that GR occupies genes involved in stem cell fate and developmental signaling, with extensive GR binding already established in quiescent SatC. GR-deficient quiescent SatC showed reduced expression of Yap1, Runx1 and Foxo1, together with increased Myog expression. Similarly, GR silencing in human myoblasts induced early myogenic differentiation markers without affecting proliferation, supporting a conserved role for GR in restraining myogenic commitment. We next examined the effects of two therapeutic GCs on muscle regeneration. Chronic prednisone treatment altered the transcriptional landscape of regenerating muscle in an age-dependent manner, without substantially affecting histological repair. In contrast, dexamethasone administration during the early inflammatory phase delayed regeneration, with persistent necrosis and increased collagen deposition. These effects were comparable in control and SatC-specific GR-deficient mice, indicating that they do not require GR in SatC. Together, these findings identify GR as a regulator of the quiescent, undifferentiated state of SatC, while showing that the effects of therapeutic GCs on muscle repair are largely independent of SatC GR. They further highlight the importance of treatment regimen and physiological context in determining the effects of GCs on skeletal muscle regeneration.

physiology↗