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GnRH neurons recruit astrocytes in infancy to facilitate network integration and sexual maturation

Nature Neuroscience volume 24, pages 1660–1672 (2021)Cite this article

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Abstract

Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D2 receptor DP1 signaling mechanism during infancy to recruit newborn astrocytes that ‘escort’ them into adulthood, and that the impairment of postnatal hypothalamic gliogenesis markedly alters sexual maturation by preventing this recruitment, a process mimicked by the endocrine disruptor bisphenol A. Inhibition of DP1 signaling in the infantile preoptic region, where GnRH cell bodies reside, disrupts the correct wiring and firing of GnRH neurons, alters minipuberty or the first activation of the hypothalamic–pituitary–gonadal axis during infancy, and delays the timely acquisition of reproductive capacity. These findings uncover a previously unknown neuron-to-neural-progenitor communication pathway and demonstrate that postnatal astrogenesis is a basic component of a complex set of mechanisms used by the neuroendocrine brain to control sexual maturation.

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Fig. 1: Postnatally born astrocytes preferentially associate with GnRH neuronal cell bodies.
Fig. 2: Inhibiting GnRH neuron association with newborn glia delays the onset of puberty and impairs mature estrous cyclicity.
Fig. 3: Early exposure to bisphenol A inhibits infantile GnRH neuron–progenitor association.
Fig. 4: Prostaglandin D2 is a chemoattractant for preoptic progenitor cells in vitro.
Fig. 5: In vivo expression of Ptgds and Ptgdr in the preoptic region of infantile female rats.
Fig. 6: Activation of DP1 signaling in the infantile preoptic region controls GnRH neuron–progenitor association, and is involved in sexual maturation.
Fig. 7: Blocking DP1 signaling in the infantile period impairs GnRH neuron maturation and functional activation.
Fig. 8: Inhibition of DP1 signaling in the infantile period leads to perturbed estrous cyclicity.

Data availability

Source data are provided with this paper, including uncropped western blots and transcriptomic data in GnV3 cells. Additional data that support the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

G.P. and M.M. were PhD students funded by the University of Lille and C.A. by the CHU Lille. We are most grateful to S. Charpier (Institut du Cerveau, UPMC-P6 UM 75, Paris, France) for precious insights in analyzing electrophysiological data and P. Giacobini (Inserm, Lille, France) for comments on the manuscript. We thank A. Dawid for data analysis (LiPhy, Grenoble), A. Caillet (U1172), N. Jouy (cytometry core facility, UMS2014-US41), M. Tardivel and A. Bongiovanni (microscopy core facility, UMS2014-US41), M. Fourdrinier (animal core facility, University of Lille) and A. Gérard (University of Liège) for expert technical assistance. We are indebted to G. Ternier for help in imaging analysis using IMARIS and to S. Nampoothiri for her work on the manuscript. This research was supported by the Fondation pour la Recherche Médicale (FRM, INE 2002), Agence Nationale de la Recherche (ANR, France) ANR-15-CE14–0025 (to V.P.), ANR-16-CE37-0006 (to V.P.), ANR-17-CE16-0015 (to V.P. and P.C.), the laboratory of excellence DISTALZ (ANR-11-LABX-0009 to V.P.) and I-SITE ULNE (ANR-16-IDEX-0004 ULNE to V.P.), the Association pour l’Etude des Anomalies Congénitales (AEAC; to A.S.) and the National Institutes of Health (1RO1 HD-084542 and 8P51OD011092 to S.R.O.).

Author information

Author notes

  1. These authors contributed equally: Giuliana Pellegrino, Marion Martin, Cécile Allet.

  2. These authors jointly supervised this work: Ariane Sharif, Vincent Prevot.

Authors and Affiliations

  1. Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, FHU 1000 Days for Health, Lille, France

    Giuliana Pellegrino, Marion Martin, Cécile Allet, Tori Lhomme, Maria Manfredi-Lozano, Adrian Coutteau-Robles, Virginia Delli, S. Rasika, Danièle Mazur, Anne Loyens, Ariane Sharif & Vincent Prevot

  2. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

    Sarah Geller

  3. Neuroendocrinology Unit, GIGA Neurosciences, University of Liège, Liège, Belgium

    Delphine Franssen & Anne-Simone Parent

  4. Service of Endocrinology, Diabetology and Metabolism, University Hospital and Faculty of Biology and Medicine, Lausanne, Switzerland

    Virginie Mansuy & François P. Pralong

  5. Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain

    Manuel Tena-Sempere

  6. Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain

    Manuel Tena-Sempere

  7. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain

    Manuel Tena-Sempere

  8. Univ. Lille, Inserm, CHU Lille, U1008, Lille, France

    Juergen Siepmann

  9. Inserm U1215, Neurocentre Magendie, Bordeaux, France

    Philippe Ciofi

  10. University of Bordeaux, Bordeaux, France

    Philippe Ciofi

  11. Kresge Hearing Research Institute, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA

    Gabriel Corfas

  12. Division of Neuroscience, Oregon National Primate Research Center-Oregon Health & Science University, Beaverton, OR, USA

    Sergio R. Ojeda

Authors
  1. Giuliana Pellegrino
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  2. Marion Martin
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  22. Vincent Prevot
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Contributions

A.S., A.-S. P. and V.P. designed the experiments. G.P., M.M., C.A., T.L., S.G., D.F., V.M., M.M.-L., A C.-R., V.D., D.M., A.L., M.T.-S., P.C., A.S. and V.P. performed the experiments. A.S. and V.P. analyzed the data. J.S., G.C. and F.P. contributed material. All authors discussed the results and edited the manuscript. A.S., S.R., S.R.O. and V.P. wrote the manuscript.

Corresponding authors

Correspondence to Ariane Sharif or Vincent Prevot.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Neuroscience thanks Margaret McCarthy, Thomas Papouin and Ei Terasawa for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Association with astrocytes sculpts the GnRH neuron environment to regulate female sexual maturation.

At the beginning of the infantile period, astrocytes in the neighborhood of GnRH neurons release glial factors that stimulate the expression of the PGD2-synthesizing enzyme, PGDS, in GnRH neurons (1). The release of PGD2 by GnRH neurons (2) promotes the DP1-dependent attraction of neighboring glial progenitors to make close contact with the GnRH neurons (3). As more progenitors differentiate into astrocytes, they provide GnRH neurons with more astrocytic factors, thus amplifying the recruitment of even more progenitors (1, 2and 3). Increased astroglial coverage promotes the establishment of excitatory glutamatergic inputs to GnRH neurons (4) and provides GnRH neurons with higher levels of the gliotransmitter PGE2 (5), known to stimulate the electrical activity of GnRH neurons32 and to be necessary for proper sexual maturation5. Schematic created with Biorender.

Supplementary information

Supplementary Information

Supplementary Note, Supplementary Figs. 1–10 and Supplementary Tables 1–3

Reporting Summary

Supplementary Data 1

A list of genes upregulated and downregulated in GnV3 cells treated with hypothalamic ACM compared to unconditioned medium. Differential hybridized features were identified using Limma, a software package that implements linear models for microarray data (two sided). The Storey and Tibshirani method was used for multiple-comparisons adjustment (Methods).

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Unprocessed western blots.

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Pellegrino, G., Martin, M., Allet, C. et al. GnRH neurons recruit astrocytes in infancy to facilitate network integration and sexual maturation. Nat Neurosci 24, 1660–1672 (2021). https://doi.org/10.1038/s41593-021-00960-z

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