1. Neuroscience

Sex specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2

  1. Silvia Leon
  2. Rajae Talbi
  3. Elizabeth A McCarthy
  4. Chrysanthi Fergani
  5. Kaitlin Ferrari
  6. Lydie Naule
  7. Ji Hae Choi
  8. Rona S Carroll
  9. Ursula B Kaiser
  10. Carlos F Aylwin
  11. Alejandro Lomniczi
  12. Víctor M Navarro  Is a corresponding author
  1. Harvard Medical School, United States
  2. Harvard Medical School and Brigham and Women's Hospital, United States
  3. Oregon National Primate Research Center, United States
https://doi.org/10.7554/eLife.69765
Share this article
Cite this article
  1. Silvia Leon
  2. Rajae Talbi
  3. Elizabeth A McCarthy
  4. Chrysanthi Fergani
  5. Kaitlin Ferrari
  6. Lydie Naule
  7. Ji Hae Choi
  8. Rona S Carroll
  9. Ursula B Kaiser
  10. Carlos F Aylwin
  11. Alejandro Lomniczi
  12. Víctor M Navarro
(2021)
Sex specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2
eLife 10:e69765.
https://doi.org/10.7554/eLife.69765
  2. Download BibTeX
  3. Download .RIS

Abstract

Hypothalamic Kiss1 neurons control gonadotropin-releasing hormone (GnRH) release through the secretion of kisspeptin. Kiss1 neurons serve as a nodal center that conveys essential regulatory cues for the attainment and maintenance of reproductive function. Despite this critical role, the mechanisms that control kisspeptin synthesis and release remain largely unknown. Using Drop-Seq data from the arcuate nucleus of adult mice and in situ hybridization, we identified Nescient Helix-Loop-Helix 2 (Nhlh2), a transcription factor (TF) of the basic helix-loop-helix family, to be enriched in Kiss1 neurons. JASPAR analysis revealed several binding sites for NHLH2 in the Kiss1 and Tac2 (neurokinin B) 5' regulatory regions. In vitro luciferase assays evidenced a robust stimulatory action of NHLH2 on human KISS1 and TAC3 promoters. The recruitment of NHLH2 to the KISS1 and TAC3 promoters was further confirmed through chromatin immunoprecipitation. In vivo conditional ablation of Nhlh2 from Kiss1 neurons using Kiss1Cre:Nhlh2fl/fl mice induced a male-specific delay in puberty onset, in line with a decrease in arcuate Kiss1 expression. Females retained normal reproductive function albeit with irregular estrous cycles. Further analysis of male Kiss1Cre:Nhlh2fl/fl mice revealed higher susceptibility to metabolic challenges in the release of luteinizing hormone (LH) and impaired response to leptin. Overall, in Kiss1 neurons, Nhlh2 contributes to the metabolic regulation of kisspeptin and NKB synthesis and release, with implications for the timing of puberty onset and regulation of fertility in male mice.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Silvia Leon

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Rajae Talbi

    Endocrinology, Harvard Medical School and Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Elizabeth A McCarthy

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Chrysanthi Fergani

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7028-4158

  5. Kaitlin Ferrari

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Lydie Naule

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Ji Hae Choi

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Rona S Carroll

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Ursula B Kaiser

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8237-0704

  10. Carlos F Aylwin

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Alejandro Lomniczi

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Víctor M Navarro

    Harvard Medical School, Boston, United States
    For correspondence
    vnavarro@bwh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5799-219X

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD090151)

  • Víctor M Navarro

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD099084)

  • Víctor M Navarro

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD095383)

  • Víctor M Navarro

Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD097963)

  • Elizabeth A McCarthy

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD084542)

  • Alejandro Lomniczi

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD019938)

  • Ursula B Kaiser

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD082314)

  • Ursula B Kaiser

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal care and experimental procedures were approved by the National Institute of Health, and Brigham and Women's Hospital Institutional Animal Care and Use Committee, protocol #05165. The Brigham and Women's Hospital is a registered research facility with the U.S. Department of Agriculture (#14-19), is accredited by the American Association for the Accreditation of Laboratory Animal Care and meets the National Institutes of Health standards as set forth in the Guide for the Care and Use of Laboratory Animals (DHHS Publication No. (NIH) 85-23 Revised 1985).

Copyright

© 2021, Leon et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,932
    views
  • 315
    downloads
  • 14
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Silvia Leon
  2. Rajae Talbi
  3. Elizabeth A McCarthy
  4. Chrysanthi Fergani
  5. Kaitlin Ferrari
  6. Lydie Naule
  7. Ji Hae Choi
  8. Rona S Carroll
  9. Ursula B Kaiser
  10. Carlos F Aylwin
  11. Alejandro Lomniczi
  12. Víctor M Navarro
(2021)
Sex specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2
eLife 10:e69765.
https://doi.org/10.7554/eLife.69765

Share this article

https://doi.org/10.7554/eLife.69765

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Rhythmic circuit function is more robust to changes in synaptic than intrinsic conductances

    Zachary Fournier, Leandro M Alonso, Eve Marder
    Research Article

    Circuit function results from both intrinsic conductances of network neurons and the synaptic conductances that connect them. In models of neural circuits, different combinations of maximal conductances can give rise to similar activity. We compared the robustness of a neural circuit to changes in their intrinsic versus synaptic conductances. To address this, we performed a sensitivity analysis on a population of conductance-based models of the pyloric network from the crustacean stomatogastric ganglion (STG). The model network consists of three neurons with nine currents: a sodium current (Na), three potassium currents (Kd, KCa, KA), two calcium currents (CaS and CaT), a hyperpolarization-activated current (H), a non-voltage-gated leak current (leak), and a neuromodulatory current (MI). The model cells are connected by seven synapses of two types, glutamatergic and cholinergic. We produced one hundred models of the pyloric network that displayed similar activities with values of maximal conductances distributed over wide ranges. We evaluated the robustness of each model to changes in their maximal conductances. We found that individual models have different sensitivities to changes in their maximal conductances, both in their intrinsic and synaptic conductances. As expected, the models become less robust as the extent of the changes increases. Despite quantitative differences in their robustness, we found that in all cases, the model networks are more sensitive to the perturbation of their intrinsic conductances than their synaptic conductances.

    1. Neuroscience

    Cognition: When working memory works for our goals

    Jacob A Miller
    Insight

    When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.

    1. Neuroscience

    Cerebellar Purkinje cells control posture in larval zebrafish (Danio rerio)

    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.