Insulin and IGF1 receptors are essential for the development and steroidogenic function of adult Leydig cells

Yasmine Neirijnck, Pierre Calvel, Karen R. Kilcoyne, Françoise Kühne, Isabelle Stévant, Richard J. Griffeth, Jean Luc Pitetti, Silvana A. Andric, Meng Chun Hu, François Pralong, Lee B. Smith, Serge Nef

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The insulin family of growth factors (insulin, IGF1, and IGF2) are critical in sex determination, adrenal differentiation, and testicular function. Notably, the IGF system has been reported to mediate the proliferation of steroidogenic cells. However, the precise role and contribution of the membrane receptors mediating those effects, namely, insulin receptor (INSR) and type-I insulin-like growth factor receptor (IGF1R), have not, to our knowledge, been investigated. We show here that specific deletion of both Insr and Igf1r in steroidogenic cells in mice leads to severe alterations of adrenocortical and testicular development. Double-mutant mice display drastic size reduction of both adrenocortex and testes, with impaired corticosterone, testosterone, and sperm production. Detailed developmental analysis of the testes revealed that fetal Leydig cell (LC) function is normal, but there is a failure of adult LC maturation and steroidogenic function associated with accumulation of progenitor LCs (PLCs). Cell-lineage tracing revealed PLC enrichment is secondary to Insr and Igf1r deletion in differentiated adult LCs, suggesting a feedback mechanism between cells at different steps of differentiation. Taken together, these data reveal the cell-autonomous and nonautonomous roles of the IGF system for proper development and maintenance of steroidogenic lineages.

Original languageEnglish
Pages (from-to)3321-3335
Number of pages15
JournalFASEB Journal
Volume32
Issue number6
DOIs
StatePublished - Jun 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© FASEB.

Funding

The authors thank Cécile Gameiro and Gregory Schneiter (Flow Cytometry Facility, University of Geneva), as well as the teams of the Bioimaging Core Facility and the Animal Facility (Faculty of Medicine, University of Geneva). This work was supported by the Swiss National Science Foundation (Grant 31003A_152636 to S.N.); the Département de l’Instruction Publique of the State of Geneva (to S.N.); and a United Kingdom Medical Research Council (UK MRC) Programme Grant Award (MR/N002970/1 to L.B.S. and K.R.K.). The authors declare no conflicts of interest.

FundersFunder number
Département de l’Instruction Publique of the State of Geneva
United Kingdom Medical Research Council (UK MRC
United Kingdom Clinical Research Collaboration
Medical Research CouncilMR/N002970/1
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung31003A_152636
Conseil Général Département des Bouches du Rhône

    Keywords

    • Adrenal gland
    • IGF
    • Progenitor Leydig cells
    • Steroidogenesis
    • Testis development

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