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Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis.

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Title: Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis.
Authors: Collado-Sole, Alejandro (AUTHOR), Borjini, Nozha (AUTHOR), Zhai, Jing (AUTHOR), Ruiz-Pino, Francisco (AUTHOR), Soria-Alcaide, Gonzalo (AUTHOR), Folgueira, Cintia (AUTHOR), García-Vilela, Celia (AUTHOR), Romero-de la Rosa, Beatriz (AUTHOR), Lopez, Victor (AUTHOR), Zouaghi, Yassine (AUTHOR), Jacobs, An (AUTHOR), Mora-Romero, Bella (AUTHOR), Barranco, Alexandra (AUTHOR), Yoldi, Guillermo (AUTHOR), Rizzoti, Karine (AUTHOR), Sabio, Guadalupe (AUTHOR), Perez-Chacon, Gema (AUTHOR), Santamaria, Patricia G. (AUTHOR), Esteban, Jose Antonio (AUTHOR), Journiac, Nathalie (AUTHOR)
Source: Science. 5/21/2026, Vol. 392 Issue 6800, p1-18. 18p.
Subjects: Microglia, Gonadotropin releasing hormone, Fertility, Developmental biology, Sex differentiation (Embryology), Hypogonadism, Hypothalamic-pituitary-gonadal axis
Abstract: The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κB (Rank) signaling. Whole-body and microglia Rank (mouse) depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK (human) in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility. Editor's summary: Pubertal development relies on the activity of the hypothalamic-pituitary-gonadal axis (HPG). Collado-Sole et al. used mouse models and human material to investigate how the HPG is regulated in the hypothalamus. The authors showed that in mice, deletion of the signaling protein Rank (receptor activator of nuclear factor κB) in microglia induced hypogonadotropic hypogonadism by modulating gonadotropin-releasing hormone function. They further validated this phenotype in patients with congenital hypogonadotropic hypogonadism. The results uncover a previously unknown role for microglia in sexual maturation. —Mattia Maroso INTRODUCTION: The brain governs sexual maturation, pubertal development, and fertility through a hormonal communication network connecting the hypothalamus, the pituitary gland, and the gonads. Disruption of the hypothalamic-pituitary-gonadal axis results in delayed or absent puberty and infertility. Gonadotropin-releasing hormone (GnRH) is the master regulator of reproduction in mammals. It is secreted in a pulsatile manner by hypothalamic GnRH neurons that release this neuropeptide at the median eminence to regulate pituitary hormone secretion and gonadal function. Although kisspeptin neurons are the main regulators of GnRH neuronal activity, the contribution of microglia, the resident immune cells of the brain, remains largely unexplored. RATIONALE: Receptor activator of nuclear factor κB (RANK) signaling is well established in bone, immune system, and mammary gland biology. This pathway is tightly regulated by sex hormones, and RANK genetic variants have been associated with timing of menarche and menopause. In the brain, RANK is predominantly expressed in microglia and can modulate microglia functionality during neuroinflammation. Given the emerging role of microglia in shaping neuronal circuits, we assessed whether RANK signaling in microglia contributes to the regulation of GnRH neurons and fertility. RESULTS: Using multiple complementary genetically modified mouse models, we found that embryonic or pubertal depletion of Rank systemically or selectively in microglia leads to severe reproductive defects. These mice displayed reduced circulating levels of sex hormones, delayed sexual maturation, and infertility, phenocopying key features of hypogonadotropic hypogonadism, a rare human reproductive disorder. Notably, we identified rare variants in the RANK gene in patients with this condition, supporting a conserved role for RANK signaling in human reproductive physiology. Single-cell transcriptional profiling following Rank loss revealed defective activation of hypothalamic microglia, accompanied by morphological alterations in the median eminence. Rank loss reduced microglia phagocytic activity, decreased microglia-GnRH neuron interactions and engulfment of GnRH terminal projections, and impaired responsiveness of GnRH neurons to kisspeptin stimulation. CONCLUSION: Our study reveals an essential role for hypothalamic microglia in the control of GnRH neuron function and fertility. We identified RANK signaling as a critical pathway enabling proper microglia activation and supporting effective GnRH neuronal activity. These findings uncover a previously unrecognized mechanism through which microglia RANK signaling regulates sexual maturation and fertility. Microglia Rank loss alters microglia activation and morphology in the median eminence, reducing GnRH-microglia contacts and impairing GnRH neuronal functionality.: This, in turn, disrupts the function of the pituitary-gonadal axis. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Label: Title
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  Data: Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis.
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  Data: <searchLink fieldCode="AR" term="%22Collado-Sole%2C+Alejandro%22">Collado-Sole, Alejandro</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Borjini%2C+Nozha%22">Borjini, Nozha</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhai%2C+Jing%22">Zhai, Jing</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ruiz-Pino%2C+Francisco%22">Ruiz-Pino, Francisco</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Soria-Alcaide%2C+Gonzalo%22">Soria-Alcaide, Gonzalo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Folgueira%2C+Cintia%22">Folgueira, Cintia</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22García-Vilela%2C+Celia%22">García-Vilela, Celia</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Romero-de+la+Rosa%2C+Beatriz%22">Romero-de la Rosa, Beatriz</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lopez%2C+Victor%22">Lopez, Victor</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zouaghi%2C+Yassine%22">Zouaghi, Yassine</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Jacobs%2C+An%22">Jacobs, An</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mora-Romero%2C+Bella%22">Mora-Romero, Bella</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Barranco%2C+Alexandra%22">Barranco, Alexandra</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yoldi%2C+Guillermo%22">Yoldi, Guillermo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Rizzoti%2C+Karine%22">Rizzoti, Karine</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sabio%2C+Guadalupe%22">Sabio, Guadalupe</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Perez-Chacon%2C+Gema%22">Perez-Chacon, Gema</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Santamaria%2C+Patricia+G%2E%22">Santamaria, Patricia G.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Esteban%2C+Jose+Antonio%22">Esteban, Jose Antonio</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Journiac%2C+Nathalie%22">Journiac, Nathalie</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 5/21/2026, Vol. 392 Issue 6800, p1-18. 18p.
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  Data: <searchLink fieldCode="DE" term="%22Microglia%22">Microglia</searchLink><br /><searchLink fieldCode="DE" term="%22Gonadotropin+releasing+hormone%22">Gonadotropin releasing hormone</searchLink><br /><searchLink fieldCode="DE" term="%22Fertility%22">Fertility</searchLink><br /><searchLink fieldCode="DE" term="%22Developmental+biology%22">Developmental biology</searchLink><br /><searchLink fieldCode="DE" term="%22Sex+differentiation+%28Embryology%29%22">Sex differentiation (Embryology)</searchLink><br /><searchLink fieldCode="DE" term="%22Hypogonadism%22">Hypogonadism</searchLink><br /><searchLink fieldCode="DE" term="%22Hypothalamic-pituitary-gonadal+axis%22">Hypothalamic-pituitary-gonadal axis</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κB (Rank) signaling. Whole-body and microglia Rank (mouse) depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK (human) in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility. Editor's summary: Pubertal development relies on the activity of the hypothalamic-pituitary-gonadal axis (HPG). Collado-Sole et al. used mouse models and human material to investigate how the HPG is regulated in the hypothalamus. The authors showed that in mice, deletion of the signaling protein Rank (receptor activator of nuclear factor κB) in microglia induced hypogonadotropic hypogonadism by modulating gonadotropin-releasing hormone function. They further validated this phenotype in patients with congenital hypogonadotropic hypogonadism. The results uncover a previously unknown role for microglia in sexual maturation. —Mattia Maroso INTRODUCTION: The brain governs sexual maturation, pubertal development, and fertility through a hormonal communication network connecting the hypothalamus, the pituitary gland, and the gonads. Disruption of the hypothalamic-pituitary-gonadal axis results in delayed or absent puberty and infertility. Gonadotropin-releasing hormone (GnRH) is the master regulator of reproduction in mammals. It is secreted in a pulsatile manner by hypothalamic GnRH neurons that release this neuropeptide at the median eminence to regulate pituitary hormone secretion and gonadal function. Although kisspeptin neurons are the main regulators of GnRH neuronal activity, the contribution of microglia, the resident immune cells of the brain, remains largely unexplored. RATIONALE: Receptor activator of nuclear factor κB (RANK) signaling is well established in bone, immune system, and mammary gland biology. This pathway is tightly regulated by sex hormones, and RANK genetic variants have been associated with timing of menarche and menopause. In the brain, RANK is predominantly expressed in microglia and can modulate microglia functionality during neuroinflammation. Given the emerging role of microglia in shaping neuronal circuits, we assessed whether RANK signaling in microglia contributes to the regulation of GnRH neurons and fertility. RESULTS: Using multiple complementary genetically modified mouse models, we found that embryonic or pubertal depletion of Rank systemically or selectively in microglia leads to severe reproductive defects. These mice displayed reduced circulating levels of sex hormones, delayed sexual maturation, and infertility, phenocopying key features of hypogonadotropic hypogonadism, a rare human reproductive disorder. Notably, we identified rare variants in the RANK gene in patients with this condition, supporting a conserved role for RANK signaling in human reproductive physiology. Single-cell transcriptional profiling following Rank loss revealed defective activation of hypothalamic microglia, accompanied by morphological alterations in the median eminence. Rank loss reduced microglia phagocytic activity, decreased microglia-GnRH neuron interactions and engulfment of GnRH terminal projections, and impaired responsiveness of GnRH neurons to kisspeptin stimulation. CONCLUSION: Our study reveals an essential role for hypothalamic microglia in the control of GnRH neuron function and fertility. We identified RANK signaling as a critical pathway enabling proper microglia activation and supporting effective GnRH neuronal activity. These findings uncover a previously unrecognized mechanism through which microglia RANK signaling regulates sexual maturation and fertility. Microglia Rank loss alters microglia activation and morphology in the median eminence, reducing GnRH-microglia contacts and impairing GnRH neuronal functionality.: This, in turn, disrupts the function of the pituitary-gonadal axis. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/science.aeb6999
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