<i>Msx1</i> and <i>Msx2</i> promote meiosis initiation

Bouffant, Ronan Le; Souquet, Benoît; Duval, Nathalie; Duquenne, Clotilde; Hervé, Roxane; Frydman, Nelly; Robert, Benoît; Habert, René; Livera, Gabriel

doi:10.1242/dev.068452

Cited by 64 publications

(57 citation statements)

References 46 publications

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“…Consistent with its function in meiosis, in Lhx8-/-ovaries we observed dysregulation of Msx1, a gene involved in promoting meiosis [49] and identified as a putative target of LHX8 [11] (Figure 2G), and another initiator of meiosis, Stra8, was earlier reported to be upregulated [10]. Furthermore, SPO11, directly involved in the induction of DNA breaks for recombination during meiosis [50], was also dysregulated at P0 in Lhx8-/-ovaries ( Figure 2G); thus, significant DNA damage was still ongoing at that stage.…”

Section: Dna Damage and Autophagysupporting

confidence: 79%

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

D'Ignazio

Michel

Beyer

et al. 2018

Biology of Reproduction

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Following proliferation of oogonia in mammals, great numbers of germ cells are discarded, primarily by apoptosis, while the remainder form primordial follicles (the ovarian reserve) that determine fertility and reproductive lifespan. More massive, rapid, and essentially total loss of oocytes, however, occurs when the transcription factor Lhx8 is ablated-though the cause and mechanism of germ cell loss from the Lhx8-/-ovaries has been unknown. We found that Lhx8−/− ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth. The loss results from activation of autophagy, which becomes overwhelming within the first postnatal week, with extracellular matrix proteins filling the space previously occupied by follicles to produce a fibrotic ovary. Associated with this process, as early as a few days before birth, Lhx8-/-oocytes failed to repair DNA damage-which normally occurs when meiosis is initiated during embryonic development; and DNA damage repair genes were downregulated throughout the oocyte short lifespan. Based on gene expression analyses and morphological changes, we propose a model in which lineage-restricted failure of DNA repair triggers germ cell autophagy, causing premature depletion of the ovarian reserve in Lhx8-/-mice. Summary SentenceAblation of Lhx8 causes premature loss of germ cells by autophagy associated with impairment of DNA damage repair during meiosis.

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Section: Dna Damage and Autophagysupporting

confidence: 79%

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

D'Ignazio

Michel

Beyer

et al. 2018

Biology of Reproduction

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“…Activation of transcription by Msx1 and Msx2 is much less documented: Msx1 and Msx2 proteins have been shown to activate the Hspa1b promoter by interacting with heat shock factors Hsf1 and Hsf2 in a DNA binding-independent manner (Zhuang et al, 2009). Furthermore, direct activation of Stra8 transcription by Msx1 and Msx2 has been described during meiosis in the female germ line (Le Bouffant et al, 2011). Our data do not rule out the possible repression of an Atoh1 repressor by Msx1 and Msx2 (Neurog1, for instance).…”

Section: Msx1 and Msx2 As Atoh1 Transcriptional Activatorscontrasting

confidence: 69%

“…6A). Furthermore, known Msx1 targets in the promoters of connexin 43 (Cx43; also known as Gja1) (Boogerd et al, 2008) and Stra8.2 (Le Bouffant et al, 2011) were not amplified (Fig. 6A), consistent with the absence of heart primordium or developing gonads from the samples analyzed.…”

Section: Msx1mentioning

confidence: 52%

Msx1 and Msx2 act as essential activators of Atoh1 expression in the murine spinal cord

et al. 2014

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Dorsal spinal neurogenesis is orchestrated by the combined action of signals secreted from the roof plate organizer and a downstream transcriptional cascade. Within this cascade, Msx1 and Msx2, two homeodomain transcription factors (TFs), are induced earlier than bHLH neuralizing TFs. Whereas bHLH TFs have been shown to specify neuronal cell fate, the function of Msx genes remains poorly defined. We describe dramatic alterations of neuronal patterning in Msx1/Msx2 double-mutant mouse embryos. The most dorsal spinal progenitor pool fails to express the bHLH neuralizing TF Atoh1, which results in a lack of Lhx2-positive and Barhl2-positive dI1 interneurons. Neurog1 and Ascl1 expression territories are dorsalized, leading to ectopic dorsal differentiation of dI2 and dI3 interneurons. In proportion, the amount of Neurog1-expressing progenitors appears unaffected, whereas the number of Ascl1-positive cells is increased. These defects occur while BMP signaling is still active in the Msx1/ Msx2 mutant embryos. Cell lineage analysis and co-immunolabeling demonstrate that Atoh1-positive cells derive from progenitors expressing both Msx1 and Msx2. In vitro, Msx1 and Msx2 proteins activate Atoh1 transcription by specifically interacting with several homeodomain binding sites in the Atoh1 3′ enhancer. In vivo, Msx1 and Msx2 are required for Atoh1 3′ enhancer activity and ChIP experiments confirm Msx1 binding to this regulatory sequence. These data support a novel function of Msx1 and Msx2 as transcriptional activators. Our study provides new insights into the transcriptional control of spinal cord patterning by BMP signaling, with Msx1 and Msx2 acting upstream of Atoh1.

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“…The albumin gene is specifically expressed in prospermatogonia of newborn testis and is not expressed in the ovary (Gelly et al, 1994;McLeod and Cooke, 1989). We also observed an increase in the premeiotic-specific mRNAs encoding STRA8, MSX1 and MSX2 (Le Bouffant et al, 2011), all of which are normally specific to female germ cells during fetal life. The RNA-Seq results for Dnmt3l and Stra8 were confirmed by using RT-qPCR.…”

Section: Bnc2 Is Required For Expression Of Dnmt3l and Repression Of mentioning

confidence: 60%

The zinc-finger protein basonuclin 2 is required for proper mitotic arrest, prevention of premature meiotic initiation and meiotic progression in mouse male germ cells

et al. 2014

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Absence of mitosis and meiosis are distinguishing properties of male germ cells during late fetal and early neonatal periods. Repressors of male germ cell meiosis have been identified, but mitotic repressors are largely unknown, and no protein repressing both meiosis and mitosis is known. We demonstrate here that the zinc-finger protein BNC2 is present in male but not in female germ cells. In testis, BNC2 exists as several spliced isoforms and presumably binds to DNA. Within the male germ cell lineage, BNC2 is restricted to prospermatogonia and undifferentiated spermatogonia. Fetal prospermatogonia that lack BNC2 multiply excessively on embryonic day (E)14.5 and reenter the cell cycle prematurely. Mutant prospermatogonia also engage in abnormal meiosis; on E17.5, Bnc2−/− prospermatogonia start synthesizing the synaptonemal protein SYCP3, and by the time of birth, many Bnc2 −/− prospermatogonia have accumulated large amounts of nonfilamentous SYCP3, thus appearing to be blocked at leptonema. Bnc2 −/− prospermatogonia do not undergo proper male differentiation, as they lack almost all the mRNA for the malespecific methylation protein DNMT3L and have increased levels of mRNAs that encode meiotic proteins, including STRA8. Bnc2 −/− prospermatogonia can produce spermatogonia, but these enter meiosis prematurely and undergo massive apoptotic death during meiotic prophase. This study identifies BNC2 as a major regulator of male germ stem cells, which is required for repression of meiosis and mitosis in prospermatogonia, and for meiosis progression during spermatogenesis. In view of the extreme evolutionary conservation of BNC2, the findings described here are likely to apply to many species.

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Msx1 and Msx2 promote meiosis initiation

Cited by 64 publications

References 46 publications

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

Msx1 and Msx2 act as essential activators of Atoh1 expression in the murine spinal cord

The zinc-finger protein basonuclin 2 is required for proper mitotic arrest, prevention of premature meiotic initiation and meiotic progression in mouse male germ cells

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