In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic dna replication

ABSTRACT The transition from mitosis to meiosis is a defining juncture in the life cycle of sexually reproducing organisms. In yeast, the decision to enter meiosis is made before the single

round of DNA replication that precedes the two meiotic divisions1. We present genetic evidence of an analogous decision point in the germ line of a multicellular organism. The mouse _Stra8_

gene is expressed in germ cells of embryonic ovaries, where meiosis is initiated, but not in those of embryonic testes, where meiosis does not begin until after birth2. Here we report that

in female embryos lacking _Stra8_ gene function, the early, mitotic development of germ cells is normal, but these cells then fail to undergo premeiotic DNA replication, meiotic chromosome

condensation, cohesion, synapsis and recombination. Combined with previous findings, these genetic data suggest that active differentiation of ovarian germ cells commences at a regulatory

point upstream of premeiotic DNA replication. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access

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subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS MAX CONTROLS MEIOTIC ENTRY IN SEXUALLY UNDIFFERENTIATED GERM CELLS Article Open access 04

March 2024 DISTINCT ROLES OF HASPIN IN STEM CELL DIVISION AND MALE GAMETOGENESIS Article Open access 06 October 2021 PRIMORDIAL GERM CELL DNA DEMETHYLATION AND DEVELOPMENT REQUIRE DNA

TRANSLESION SYNTHESIS Article Open access 03 May 2024 REFERENCES * Marston, A.L. & Amon, A. Meiosis: cell-cycle controls shuffle and deal. _Nat. Rev. Mol. Cell Biol._ 5, 983–997 (2004).

Article  CAS  Google Scholar  * Menke, D.B., Koubova, J. & Page, D.C. Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave. _Dev. Biol._ 262,

303–312 (2003). Article  CAS  Google Scholar  * McLaren, A. & Southee, D. Entry of mouse embryonic germ cells into meiosis. _Dev. Biol._ 187, 107–113 (1997). Article  CAS  Google Scholar

  * Adams, I.R. & McLaren, A. Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. _Development_ 129, 1155–1164 (2002). CAS  PubMed

  Google Scholar  * Koubova, J. et al. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. _Proc. Natl. Acad. Sci. USA_ 103, 2474–2479 (2006). Article  CAS  Google

Scholar  * Bowles, J. et al. Retinoid signaling determines germ cell fate in mice. _Science_ 312, 596–600 (2006). Article  CAS  Google Scholar  * Yao, H.H., DiNapoli, L. & Capel, B.

Meiotic germ cells antagonize mesonephric cell migration and testis cord formation in mouse gonads. _Development_ 130, 5895–5902 (2003). Article  CAS  Google Scholar  * Bullejos, M. &

Koopman, P. Germ cells enter meiosis in a rostro-caudal wave during development of the mouse ovary. _Mol. Reprod. Dev._ 68, 422–428 (2004). Article  CAS  Google Scholar  * Oulad-Abdelghani,

M. et al. Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by _Stra8_, a novel retinoic acid-responsive gene. _J. Cell Biol._ 135, 469–477 (1996). Article  CAS

  Google Scholar  * Hartung, M. & Stahl, A. Preleptotene chromosome condensation in mouse oogenesis. _Cytogenet. Cell Genet._ 18, 309–319 (1977). Article  CAS  Google Scholar  *

Devictor, M., Luciani, J.M. & Stahl, A. Do male germ cells begin meiosis during fetal life? _J. Genet. Hum._ 27, 21–28 (1979). CAS  PubMed  Google Scholar  * Borum, K. Oogenesis in the

mouse. A study of the meiotic prophase. _Exp. Cell Res._ 24, 495–507 (1961). Article  CAS  Google Scholar  * Speed, R.M. Meiosis in the foetal mouse ovary. I. An analysis at the light

microscope level using surface-spreading. _Chromosoma_ 85, 427–437 (1982). Article  CAS  Google Scholar  * Eijpe, M., Offenberg, H., Jessberger, R., Revenkova, E. & Heyting, C. Meiotic

cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1beta and SMC3. _J. Cell Biol._ 160, 657–670 (2003). Article  CAS  Google Scholar  * Lee, J., Iwai, T.,

Yokota, T. & Yamashita, M. Temporally and spatially selective loss of _Rec8_ protein from meiotic chromosomes during mammalian meiosis. _J. Cell Sci._ 116, 2781–2790 (2003). Article 

CAS  Google Scholar  * Moens, P.B. & Spyropoulos, B. Immunocytology of chiasmata and chromosomal disjunction at mouse meiosis. _Chromosoma_ 104, 175–182 (1995). Article  CAS  Google

Scholar  * Prieto, I. et al. Cohesin component dynamics during meiotic prophase I in mammalian oocytes. _Chromosome Res._ 12, 197–213 (2004). Article  CAS  Google Scholar  * Rogakou, E.P.,

Pilch, D.R., Orr, A.H., Ivanova, V.S. & Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. _J. Biol. Chem._ 273, 5858–5868 (1998). Article  CAS 

Google Scholar  * Pittman, D.L. et al. Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for _Dmc1_, a germline-specific RecA homolog. _Mol. Cell_ 1, 697–705

(1998). Article  CAS  Google Scholar  * Yoshida, K. et al. The mouse RecA-like gene _Dmc1_ is required for homologous chromosome synapsis during meiosis. _Mol. Cell_ 1, 707–718 (1998).

Article  CAS  Google Scholar  * Baudat, F., Manova, K., Yuen, J.P., Jasin, M. & Keeney, S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking _Spo11_.

_Mol. Cell_ 6, 989–998 (2000). Article  CAS  Google Scholar  * Romanienko, P.J. & Camerini-Otero, R.D. The mouse _Spo11_ gene is required for meiotic chromosome synapsis. _Mol. Cell_ 6,

975–987 (2000). Article  CAS  Google Scholar  * Crone, M., Levy, E. & Peters, H. The duration of the premeiotic DNA synthesis in mouse oocytes. _Exp. Cell Res._ 39, 678–688 (1965).

Article  CAS  Google Scholar  * Toyooka, Y. et al. Expression and intracellular localization of mouse Vasa-homologue protein during germ cell development. _Mech. Dev._ 93, 139–149 (2000).

Article  CAS  Google Scholar  * Bannister, L.A., Reinholdt, L.G., Munroe, R.J. & Schimenti, J.C. Positional cloning and characterization of mouse _mei8_, a disrupted allelle of the

meiotic cohesin _Rec8_. _Genesis_ 40, 184–194 (2004). Article  CAS  Google Scholar  * Yuan, L. et al. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis,

and male fertility. _Mol. Cell_ 5, 73–83 (2000). Article  CAS  Google Scholar  * Xu, H., Beasley, M.D., Warren, W.D., van der Horst, G.T. & McKay, M.J. Absence of mouse REC8 cohesin

promotes synapsis of sister chromatids in meiosis. _Dev. Cell_ 8, 949–961 (2005). Article  CAS  Google Scholar  * Brennan, J. & Capel, B. One tissue, two fates: molecular genetic events

that underlie testis versus ovary development. _Nat. Rev. Genet._ 5, 509–521 (2004). Article  CAS  Google Scholar  * Fujiwara, S. & Kawamura, K. Acquisition of retinoic acid signaling

pathway and innovation of the chordate body plan. _Zoolog. Sci._ 20, 809–818 (2003). Article  CAS  Google Scholar  * Albrecht, K.H. & Eicher, E.M. Evidence that _Sry_ is expressed in

pre-Sertoli cells and Sertoli and granulosa cells have a common precursor. _Dev. Biol._ 240, 92–107 (2001). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank R.

Jaenisch (Whitehead Institute for Biomedical Research) for v6.5 ES cells; A. Bortvin, T. Hassold and T. Ashley for advice; C. Heyting (Department of Genetics, Agricultural University,

Wageningen) for SCP3 and REC8 antisera; T. Noce (Mitsubishi Kagaku Institute of Life Science) for MVH antisera and E. Anderson, G. Baltus, M. Capelson, M. Gill, J. Koubova, J. Lange, Y. Lim,

J. Mueller and J. Potash for comments on the manuscript. Microscopy and image capture were conducted in part at the W.M. Keck Foundation Biological Imaging Facility at the Whitehead

Institute. A.E.C. is a Novartis Fellow of the Life Sciences Research Foundation. This work was supported by the Howard Hughes Medical Institute. AUTHOR INFORMATION Author notes * Andrew E

Baltus and Douglas B Menke: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Howard Hughes Medical Institute, Cambridge, 02142, Massachusetts, USA Andrew E Baltus, 

Douglas B Menke, Yueh-Chiang Hu, Mary L Goodheart & David C Page * Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge,

02142, Massachusetts, USA Andrew E Baltus, Douglas B Menke, Yueh-Chiang Hu, Mary L Goodheart, Anne E Carpenter & David C Page * Departments of Endocrinology, Faculty of Biology, Utrecht

University and of Cell Biology, University Medical Centre Utrecht, Utrecht, 3584 CH, The Netherlands Dirk G de Rooij Authors * Andrew E Baltus View author publications You can also search

for this author inPubMed Google Scholar * Douglas B Menke View author publications You can also search for this author inPubMed Google Scholar * Yueh-Chiang Hu View author publications You

can also search for this author inPubMed Google Scholar * Mary L Goodheart View author publications You can also search for this author inPubMed Google Scholar * Anne E Carpenter View author

publications You can also search for this author inPubMed Google Scholar * Dirk G de Rooij View author publications You can also search for this author inPubMed Google Scholar * David C

Page View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to David C Page. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIG. 1 Targeted disruption of the _Stra8_ locus. (PDF 781 kb) SUPPLEMENTARY FIG. 2 Germ cell loss

and reduced gonadal size in _Stra8_-deficient mice. (PDF 876 kb) SUPPLEMENTARY FIG. 3 Alignment of predicted amino acid sequences of STRA8 homologs identified electronically. (PDF 105 kb)

SUPPLEMENTARY TABLE 1 Oligonucleotide sequences. (PDF 35 kb) SUPPLEMENTARY NOTE (PDF 65 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Baltus, A.,

Menke, D., Hu, YC. _et al._ In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. _Nat Genet_ 38, 1430–1434 (2006).

https://doi.org/10.1038/ng1919 Download citation * Received: 28 August 2006 * Accepted: 06 October 2006 * Published: 19 November 2006 * Issue Date: 01 December 2006 * DOI:

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