Yoldi, G. | Search bioRxiv

bioRxiv2026

Microglia Rank signaling regulates GnRH function and the Hypothalamic-Pituitary-Gonadal axis

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We hereby demonstrate a new role of hypothalamic microglia in controlling the HPG axis through Rank signaling, a pathway known for its role in bone and mammary gland biology. Whole-body and microglia Rank depletion leads to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) function. In addition, we identify rare gene variants of RANK in patients with HH. Transcriptional profiling upon pubertal Rank loss reveals defective microglia activation and morphological alterations in the median eminence (ME), decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH responses to kisspeptin. Overall, our data uncovers the crucial role of microglia in regulating GnRH function through Rank signaling, with implications for reproductive maturation and fertility. One-Sentence SummaryMicroglia regulates GnRH function through RANK signaling

cell biology↗

bioRxiv2022

The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Endometrial cancer (EC) is the most common type of gynaecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel molecular therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different forms of stress, including oxidative stress and cytokines. Previous evidence support a role for the MEK5-ERK5 pathway in the pathology of several cancers. We have investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition decreased EGF-induced EC cell proliferation, and that depletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic or genetic silencing of ERK5 impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, impairment of ERK5 resulted in downregulation of NEMO/IKK{gamma} expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKK{gamma} overexpression. Notably, ERK5 inhibition, MEK5 depletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-{kappa}B pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-{kappa}B axis as new target for EC treatment.

cancer biology↗