Response to: X‐linked miR‐506 family miRNAs promote FMRP expression in mouse spermatogonia

Abstract

EMBO Reports (2020) 21: e49354Reply to: Z Wang et al T he topic of this rebuttal is a set of miRNAs expressed from a large gene cluster located in the Fragile-X region of the X chromosome that we call the "Fragile-X miRNA (Fx-mir) cluster". This miRNA cluster has several other names. Wang et al calls them the "miR-506 family", as some members of this cluster are related to this particular miRNA. Other names for this cluster from recent papers are "spermiR" [1] and "XmiR" [2].In our Ramaiah et al [3] paper, we reported several lines of evidence that four members of the Fx-mir cluster-miR-741-3p, -743b-3p, -878-5p, and -880-3p-are highly expressed in Sertoli cells (SCs), where they target the adjacent gene Fmr1. The Wang et al rebuttal claims that most members of the Fx-mir cluster and the Fmr1 gene are instead primarily expressed in germ cells (GCs). Below, we go over the evidence both for and against these claims.

X‐linked miR‐506 family miRNAs promote FMRP expression in mouse spermatogonia

“…Second, the authors demonstrated that the miR-506 family miRNAs showed elevated levels in germ cell-deficient testes of mice (jsd/jsd mice) and humans (Sertoli cell-only (SCO) patients) compared with normal controls. However, the testes of jsd/jsd mice are known to contain some spermatogonia, albeit in a small number [13], and SCO human testes may also contain some germ cells, as acknowledged by the authors as well [5]. Therefore, qPCR-based detection of the miR-506 family miRNAs in these so-called germ cell-deficient testes cannot exclude their expression in spermatogonia.…”

“…The close proximity between the miR-506 family and Fmr1 has prompted a hypothesis that Fmr1 might be a target of the miR-506 family. A recent paper by Ramaiah et al reports that the miR-506 family miRNAs, which they termed Fx-mir miRNAs, function to repress Fmr1 (encoding FMRP) expression in Sertoli cells based on expression profiling analyses and luciferase-based reporter assays in vitro [5]. Our laboratory first reported the exclusive or preferential expression of 77 Xlinked miRNAs in the murine testes [3], and we happen to have generated knockout (KO) mice lacking the five miRNA clusters encoding 18 out of 21 miR-506 family miRNAs.…”

“…For example, the miR-506 family contains 21 miRNAs that are transcribed from five large miRNA clusters encompassing a ~62 kb region near Slitrk2 and one large miRNA cluster expanding ~22 kb region close to Fmr1 on the X chromosome [4] (Fig 1A, Table EV1). Although miR-506 family miRNAs have undergone rapid evolution, the two proteincoding genes flanking these miRNA clusters, i.e., Fmr1 and Slitrk2, remain highly conserved across all mammalian species [5,6]. Fmr1 and Slitrk2 are known to be involved in human fragile X mental retardation [7] and Tourette's syndrome [8], respectively.…”