Interference with lactate metabolism by mmu-miR-320-3p via negatively regulating GLUT3 signaling in mouse Sertoli cells

Li-Li Zhang,Jing Ma,Yuan-Qiang Zhang,Bo Yang,Bin-Yuan Yan,Jie Zhao,Wei Li

doi:10.1038/s41419-018-0958-2

Li-Li Zhang, Jing Ma + Show 5 more

Open Access

https://doi.org/10.1038/s41419-018-0958-2

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Abstract

Disruption of the nursery function in Sertoli cells (SCs) by reducing lactate production, a preferred energy substrate for developed germ cells (spermatocytes and spermatids), is tightly associated with spermatogenic failure such as SC-only syndrome (SCOS). However, whether this complicated pathogenesis is regulated by certain miRNAs at the post-transcriptional level remain fascinating but largely unknown. Here we show for the first time that mmu-miR-320-3p was exclusively expressed in murine SCs and this expression was significantly induced in busulphan-treated murine testis. The most efficient stimulatory germ cell types for the induction of apoptosis-elicited mmu-miR-320-3p expression were meiotic spermatocytes and haploid spermatids. Functionally, forced expression of the exogenous mmu-miR-320-3p in SCs compromises male fertility by causing oligozoospermia and defection of sperm mobility. Mechanistically, mmu-miR-320-3p negatively regulates lactate production of SCs by directly inhibiting glucose transporter 3 (GLUT3) expression. Thus, dysregulation of mmu-miR-320-3p/GLUT3 cascade and consequently of lactate deficiency may be a key molecular event contributing the germ cell loss by SC dysfunction. Future endeavor in the continuous investigation of this important circulating miRNA may shed novel insights into epigenetic regulation of SCs nursery function and the etiology of azoospermia, and offers novel therapeutic and prognostic targets for SCOS.

Highlights

Known as “nurse cells”, the Sertoli cells (SCs) play a crucial role on the nutritional support of germ cells (GCs) during the each stage of spermatogenesis
specific primers for Rhox5 (SCs) During the course of studying the potential posttranscriptional regulatory mechanisms in testicular tissues from infertile patients, we unexpectedly found that hsa-miR-320c-3p expression was significantly increased in testicular tissues from SC-only syndrome (SCOS) patients compared with that in the normal testes (Supplementary Fig. 1A and 1B, 1.57 ± 0.59 vs. 0.87 ± 0.36, P < 0.0001, Student’s t-test)
Given that murine SCs are considered to be terminally differentiated during puberty[17], our results indicate that miR-320-3p expression correlates well to the sufficient acquirement of SC function

Summary

Introduction

Known as “nurse cells”, the Sertoli cells (SCs) play a crucial role on the nutritional support of germ cells (GCs) during the each stage of spermatogenesis. GCs exist in an environment created by SCs, so paracrine signaling between these intimately associated cells must regulate the proliferation and apoptosis in GCs4. In this context, it has been suggested that dysfunction of certain genetic factors and consequent impairment of SC function Zhang et al Cell Death and Disease (2018)9:964 junction formation) may play causative roles in spermatogenic failure[5]. The molecular mechanisms controlling SCs function remain largely unknown

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