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Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice

Author

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  • Juan Roa

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Miguel Ruiz-Cruz

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Francisco Ruiz-Pino

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Rocio Onieva

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Maria J. Vazquez

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Maria J. Sanchez-Tapia

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Jose M. Ruiz-Rodriguez

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Veronica Sobrino

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Alexia Barroso

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Violeta Heras

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Inmaculada Velasco

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Cecilia Perdices-Lopez

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Claes Ohlsson

    (Sahlgrenska Academy, University of Gothenburg)

  • Maria Soledad Avendaño

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Vincent Prevot

    (Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition)

  • Matti Poutanen

    (Sahlgrenska Academy, University of Gothenburg
    University of Turku)

  • Leonor Pinilla

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Francisco Gaytan

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Manuel Tena-Sempere

    (Instituto Maimónides de Investigación Biomédica de Córdoba
    University of Córdoba
    Hospital Universitario Reina Sofia
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

Abstract

Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1/kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function.

Suggested Citation

  • Juan Roa & Miguel Ruiz-Cruz & Francisco Ruiz-Pino & Rocio Onieva & Maria J. Vazquez & Maria J. Sanchez-Tapia & Jose M. Ruiz-Rodriguez & Veronica Sobrino & Alexia Barroso & Violeta Heras & Inmaculada V, 2022. "Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32347-4
    DOI: 10.1038/s41467-022-32347-4
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    References listed on IDEAS

    as
    1. Carlos A. Toro & Hollis Wright & Carlos F. Aylwin & Sergio R. Ojeda & Alejandro Lomniczi, 2018. "Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    2. Brenda J. Reinhart & Frank J. Slack & Michael Basson & Amy E. Pasquinelli & Jill C. Bettinger & Ann E. Rougvie & H. Robert Horvitz & Gary Ruvkun, 2000. "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans," Nature, Nature, vol. 403(6772), pages 901-906, February.
    3. M. J. Vazquez & C. A. Toro & J. M. Castellano & F. Ruiz-Pino & J. Roa & D. Beiroa & V. Heras & I. Velasco & C. Dieguez & L. Pinilla & F. Gaytan & R. Nogueiras & M. A. Bosch & O. K. Rønnekleiv & A. Lom, 2018. "SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
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