The germ cell-specific RNA binding protein RBM46 is essential for spermatogonial differentiation in mice

Peart, Natoya; Johnson, Taylor A.; Lee, SungKyoung; Sears, Matthew J.; Fang, Yang; Quesnel-Vallières, Mathieu; Feng, Huijuan; Recinos, Yocelyn; Barash, Yoseph; Zhang, Chaolin; Hermann, Brian P.; Wang, P. Jeremy; Geyer, Christopher B.; Carstens, Russ P.

doi:10.1371/journal.pgen.1010416

Cited by 6 publications

(5 citation statements)

References 82 publications

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“…By meiotic prophase I, Meioc-null germ cells exhibited delayed upregulation of Meiosin expression (Fig.4A). We confirmed that Meiosin expression is also increased by YTHDC2 and RBM46, based on previously reported analyses of bulk RNA-seq data from postnatal testes(Jain et al 2018;Peart et al 2022). MEIOC does not bind Meiosin mRNA, nor does MEIOC affect other known regulators of Meiosin gene expression (i.e., retinoic acid-dependent transcription and DMRT1 activity; Fig.…”

supporting

confidence: 90%

Destabilization of mRNAs enhances competence to initiate meiosis in mouse spermatogenic cells

Pfaltzgraff,

Liu,

de Rooij

et al. 2023

Preprint

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The special cell cycle known as meiosis transforms diploid germ cells into haploid gametes. In mammalian testes, diploid spermatogenic cells become competent to transition from mitosis to meiosis in response to retinoic acid. In mice, previous studies revealed that MEIOC, alongside binding partners YTHDC2 and RBM46, represses mitotic genes and promotes robust meiotic gene expression in spermatogenic cells that have already initiated meiosis. Here, we molecularly dissect MEIOC-dependent regulation in mouse spermatogenic cells and find that MEIOC actually shapes the transcriptome much earlier, even before meiotic initiation. MEIOC, acting with YTHDC2 and RBM46, destabilizes mRNA targets, including transcriptional repressors E2f6 and Mga, in mitotic spermatogonia. MEIOC thereby derepresses E2F6- and MGA-repressed genes, including Meiosin and other meiosis-associated genes. This confers on spermatogenic cells the molecular competence to, in response to retinoic acid, fully activate the STRA8-MEIOSIN transcriptional regulator, which is required for the meiotic G1/S cell cycle transition and meiotic gene expression. We conclude that in mice, mRNA decay mediated by MEIOC-YTHDC2-RBM46 enhances the competence of mitotic spermatogonia to transit from mitosis to meiosis.

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supporting

confidence: 90%

Destabilization of mRNAs enhances competence to initiate meiosis in mouse spermatogenic cells

Pfaltzgraff,

Liu,

de Rooij

et al. 2023

Preprint

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“…Immunostaining was performed as before [10,[35][36][37]. Briefly, PFA-fixed testes were washed in 1X PBS overnight, soaked in 30% sucrose for 24 h, and frozen in O.C.T.…”

Section: Indirect Immunofluorescencementioning

confidence: 99%

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

Johnson

Niedenberger

Kirsanov

et al. 2023

Biology of Reproduction

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The foundation of mammalian spermatogenesis is provided by undifferentiated spermatogonia, comprised of spermatogonial stem cells (SSCs) and transit-amplifying progenitors that differentiate in response to retinoic acid (RA) and are committed to enter meiosis. Our laboratory recently reported that the foundational populations of SSCs, undifferentiated progenitors, and differentiating spermatogonia are formed in the neonatal testis in part based on their differential responsiveness to RA. Here, we expand on those findings to define the extent to which RA responsiveness during steady-state spermatogenesis in the adult testis regulates spermatogonial fate. Our results reveal both progenitor and differentiating spermatogonia throughout the testis are capable of responding to exogenous RA, but their resulting fates were quite distinct – undifferentiated progenitors precociously differentiated and proceeded into meiosis on a normal timeline, while differentiating spermatogonia were unable to hasten their entry into meiosis. This reveals spermatogonia responding to RA must still complete the 8.6 day differentiation program prior to their entry into meiosis. Addition of exogenous RA enriched testes with preleptotene and pachytene spermatocytes one and two seminiferous cycles later, respectively, supporting recent clinical studies reporting increased sperm production and enhanced fertility in subfertile men on long-term RA analog treatment. Collectively, our results reveal a well-buffered system exists within mammalian testes to regulate spermatogonial RA exposure, that exposed undifferentiated progenitors can precociously differentiate, but must complete a normal-length differentiation program prior to entering meiosis, and that daily RA treatments increased numbers of advanced germ cells by directing undifferentiated progenitors to continuously differentiate.

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“…Binding of YTHDC2 to both MEIOC and RBM46 does not require RNA. Meioc and Rbm46 knockout males show the same early spermatocyte death phenotype as Ythdc2 null mutants (Abby et al, 2016;Peart et al, 2022;Qian et al, 2022;Soh et al, 2017), suggesting that YTHDC2, MEIOC and RBM46 function together to regulate the switch from mitosis to meiosis in males. Directly tying YTHDC2 target RNAs to degradation machinery and supporting a functional role for YTHDC2 in regulating RNA stability, previous studies have also shown that the cytoplasmic 5ʹ → 3ʹ exoribonuclease XRN1 is a direct, RNA-independent binding partner of YTHDC2, interacting via the YTHDC2 ANK domain (Kretschmer et al, 2018;Li et al, 2022;Wojtas et al, 2017).…”

Section: Introductionmentioning

confidence: 96%

YTHDC2 serves a distinct late role in spermatocytes during germ cell differentiation

Bailey

Fuller

2023

Preprint

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Post-transcriptional regulation of gene expression by RNA-binding proteins helps facilitate fast, clean transitions from one cell state to the next during germ cell differentiation. Previously we showed that the RNA helicase YTHDC2 is required for germ cells to properly switch from mitosis to meiosis (Bailey et al., 2017). While YTHDC2 protein is first expressed as male germ cells enter meiosis, when it is needed to shut down the mitotic program, YTHDC2 expression continues to increase and reaches its highest levels later in meiotic prophase, in pachytene spermatocytes. Here we show that YTHDC2 has an additional essential role regulating meiotic progression in late spermatocytes during mouse germ cell differentiation. Inducing conditional knockout ofYthdc2during the first wave of spermatogenesis, after the germ cells have already initiated meiotic prophase, allowedYthdc2-deficient germ cells to successfully reach the pachytene stage and properly express many meiotic markers. However, instead of continuing through meiotic prophase and initiating the meiotic divisions, late pachytene spermatocytes failed to transition to the diplotene stage and quickly died. Loss of function ofYthdc2in spermatocytes resulted in changes in transcript levels for a number of genes, some up-regulated and some down-regulated, compared to control mid-stage spermatocytes. YTHDC2 interacts with different proteins in early and late spermatocytes, with many of the interacting proteins involved in post-transcriptional RNA regulation and present in RNA granules, similar to YTHDC2. Our findings suggest that YTHDC2 facilitates proper progression of germ cells through multiple steps of meiosis, potentially via several mechanisms of post-transcriptional RNA regulation.

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The germ cell-specific RNA binding protein RBM46 is essential for spermatogonial differentiation in mice

Cited by 6 publications

References 82 publications

Destabilization of mRNAs enhances competence to initiate meiosis in mouse spermatogenic cells

Destabilization of mRNAs enhances competence to initiate meiosis in mouse spermatogenic cells

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

YTHDC2 serves a distinct late role in spermatocytes during germ cell differentiation

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