Leagues of their own: sexually dimorphic features of meiotic prophase I

Cahoon, Cori K.; Libuda, Diana E.

doi:10.1007/s00412-019-00692-x

Cited by 30 publications

(43 citation statements)

References 127 publications

(187 reference statements)

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“…This raises the possibility that meiotic progression is regulated differently between the sexes. Consistent with this, sexual dimorphisms in meiosis, such as the number of crossovers per nucleus, axis length of meiotic chromosomes, and recombination rate, have been reported in several animals (25)(26)(27)(28)(29). Although the molecular mechanisms responsible for generating such sexual dimorphisms have not been elucidated, functional investigation of rec8a may provide insight into the role of sexual dimorphisms in meiosis.…”

Section: Discussionsupporting

confidence: 55%

foxl3 , a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka

Kikuchi

Nishimura

Ishishita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Germ cells have the ability to differentiate into eggs and sperm and must determine their sexual fate. In vertebrates, the mechanism of commitment to oogenesis following the sexual fate decision in germ cells remains unknown.Forkhead-box protein L3(foxl3) is a switch gene involved in the germline sexual fate decision in the teleost fish medaka (Oryzias latipes). Here, we show thatfoxl3organizes two independent pathways of oogenesis regulated byREC8 meiotic recombination protein a(rec8a), a cohesin component, andF-box protein(FBP) 47(fbxo47), a subunit of E3 ubiquitin ligase. In mutants of either gene, germ cells failed to undergo oogenesis but developed normally into sperm in testes. Disruption ofrec8aresulted in arrest at a meiotic pachytenelike stage specifically in females, revealing a sexual difference in meiotic progression. Analyses offbxo47mutants showed that this gene regulates transcription factors that facilitate folliculogenesis:LIM homeobox 8(lhx8b),factor in the germlineα (figla), andnewborn ovary homeobox(nobox). Interestingly, we found that thefbxo47pathway ensures that germ cells do not deviate from an oogenic pathway until they reach diplotene stage. The mutant phenotypes together with the timing of their expression imply that germline feminization is established during early meiotic prophase I.

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Section: Discussionsupporting

confidence: 55%

foxl3 , a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka

Kikuchi

Nishimura

Ishishita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Others have recently reported phenotyping of Zcwpw1 -/mice (M. , and although our KO is different, we observe similar patterns of infertility in males, and results consistent with gradual fertility decline in females, towards sterility from 8 months onwards. Why females deficient for ZCWPW1 are (at least initially) fertile is unknown, but resembles sexual dimorphism in loss-of-function mutants for other meiotic genes involved in homologous recombination, where females exhibit a milder fertility phenotype (Cahoon and Libuda, 2019;Morelli and Cohen, 2005;Zhang et al, 2019). However we observe a distinct intracellular localisation of ZCWPW1 from that reported by (M. : while we also detect ZCWPW1 as a diffuse nuclear signal across the nucleus (though excluding the chromocenters) and localisation to the XY body in pachytene, we see an additional signal in mid-pachytene to diplotene cells at the ends of the synaptonemal complex.…”

Section: Discussionmentioning

confidence: 99%

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

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During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified.We identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons.Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility. Graphical Abstract LegendIn humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

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“…The observed sexual dimorphism of HSF2BP and MIDAP mutants has also been described for several other meiotic genes in the mouse (Cahoon and Libuda, 2019). These differences can have a structural basis, given that the organization of the axial elements is known to be different between sexes.…”

Section: Discussionmentioning

confidence: 65%

“…These variants should be under purifying selection and would be removed or substantially reduced from the population. However, this is not the case for genes with sexual phenotypic dimorphism (Gershoni and Pietrokovski, 2014) as is apparent for a wide number of meiotic genes, including HSF2BP and MIDAP (Cahoon and Libuda, 2019), where individuals of one of the sexes are fertile carriers.…”

Section: Discussionmentioning

confidence: 99%

A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

Felipe‐Medina¹,

Caburet

Sánchez-Sáez³

et al. 2020

Preprint

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Felipe-Medina et al. describe a missense variant in the meiotic gene HSF2BP in a consanguineous family with Premature Ovarian Insufficiency, and characterize it as an hypormorphic allele, that in vivo impairs its dimerization with a novel meiotic actor, MIDAP/ C19ORF57, and affect recombination at double-strand DNA breaks. AbstractPrimary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene.Functional analysis of the HSF2BP-S167L variant in mouse, compared to a new HSF2BP knock-out mouse showed that it behaves as a hypomorphic allele. HSF2BP-S167L females show reduced fertility with small litter sizes. To obtain mechanistic insights, we identified C19ORF57/MIDAP as a strong interactor and stabilizer of HSF2BP by forming a higherorder macromolecular structure involving BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L mutation showed a strongly decreased expression of both MIDAP and HSF2BP at the recombination nodules. Although HSF2BP-S167L does not affect heterodimerization between HSF2BP and MIDAP, it promotes a lower expression of both proteins and a less proficient activity in replacing RPA by the recombinases RAD51/DMC1, thus leading to a lower frequency of cross-overs. Our results provide insights into the molecular mechanism of two novel actors of meiosis underlying non-syndromic ovarian insufficiency.

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Leagues of their own: sexually dimorphic features of meiotic prophase I

Cited by 30 publications

References 127 publications

foxl3 , a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka

foxl3 , a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

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