Irregular telomeres impair meiotic synapsis and recombination in mice.

Telomere shortening can lead to chromosome instability, replicative senescence, and apoptosis in both somatic and male germ cells. To study roles for mammalian telomeres in homologous pairing and recombination, we characterized effects of telomere shortening on spermatogenesis and oogenesis in late-generation telomerase-deficient mice. We show that shortened telomeres of late-generation telomerase-deficient mice impair meiotic synapsis and decrease recombination, in particular, in females. In response to telomere shortening, male germ cells mostly undergo apoptosis, whereas female germ cells preferentially arrest in early meiosis, suggesting sexually dimorphic surveillance mechanisms for telomere dysfunction during meiosis in mice. Further, meiocytes of late-generation telomerase-deficient females with shortened telomeres, bred with early-generation males harboring relatively long telomeres, exhibit severely impaired chromosome pairing and synapsis and reduced meiotic recombination. These findings imply that functional telomeres are important in mammalian meiotic synapsis and recombination.

[1]  P. de Boer,et al.  SHORT COMMUNICATIONS A drying-down technique for the spreading of mammalian meiocytes from the male and female germline , 1997, Chromosome Research.

[2]  Roeder Gs Meiotic chromosomes: it takes two to tango , 1997 .

[3]  R. Pearlman,et al.  Telomere and centromere DNA are associated with the cores of meiotic prophase chromosomes , 1990, Chromosoma.

[4]  Margaret A. Strong,et al.  Telomere dysfunction triggers developmentally regulated germ cell apoptosis. , 2001, Molecular biology of the cell.

[5]  L. Anderson,et al.  Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. , 1999, Genetics.

[6]  G. D. Stewart,et al.  A genetic linkage map of human chromosome 21: analysis of recombination as a function of sex and age. , 1992, American journal of human genetics.

[7]  N. Kleckner,et al.  Meiotic chromosomes: integrating structure and function. , 1999, Annual review of genetics.

[8]  P. Moens,et al.  In situ hybridization of meiotic prophase chromosomes. , 1994, Methods in molecular biology.

[9]  T. Lange Ending up with the right partner , 1998, Nature.

[10]  M. Hande,et al.  Telomere Length Dynamics and Chromosomal Instability in Cells Derived from Telomerase Null Mice , 1999, The Journal of cell biology.

[11]  B. Daneholt,et al.  The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. , 2000, Molecular cell.

[12]  E. Blackburn,et al.  Telomere states and cell fates , 2000, Nature.

[13]  R K Ward,et al.  Telomere length measurements using digital fluorescence microscopy. , 1999, Cytometry.

[14]  Geraldine M Hartshorne,et al.  Patterns of meiotic recombination in human fetal oocytes. , 2002, American journal of human genetics.

[15]  M. Hultén,et al.  Combined immunocytogenetic and molecular cytogenetic analysis of meiosis I human spermatocytes , 1996, Chromosome Research.

[16]  María A Blasco,et al.  Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA , 1997, Cell.

[17]  R. Kucherlapati,et al.  Mammalian MutS homologue 5 is required for chromosome pairing in meiosis , 1999, Nature Genetics.

[18]  M. Blasco,et al.  Telomere length abnormalities in mammalian radiosensitive cells. , 2001, Cancer research.

[19]  J. Hodgkin,et al.  MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans , 2000, Nature.

[20]  M. Blasco,et al.  Requirement of functional telomeres for metaphase chromosome alignments and integrity of meiotic spindles , 2002, EMBO reports.

[21]  A. Spradling,et al.  Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles. , 2001, Developmental biology.

[22]  P. Cohen,et al.  The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination. , 2002, Journal of cell science.

[23]  D. Ward,et al.  Molecular characterization of a pericentric inversion in mouse chromosome 8 implicates telomeres as promoters of meiotic recombination , 2004, Chromosoma.

[24]  H. Scherthan,et al.  Mammalian meiotic telomeres: protein composition and redistribution in relation to nuclear pores. , 2000, Molecular biology of the cell.

[25]  G. Roeder,et al.  Telomere-mediated chromosome pairing during meiosis in budding yeast. , 1998, Genes & development.

[26]  R. DePinho,et al.  Essential role of mouse telomerase in highly proliferative organs , 1998, Nature.

[27]  C. Heyting,et al.  A Meiotic Chromosomal Core Consisting of Cohesin Complex Proteins Recruits DNA Recombination Proteins and Promotes Synapsis in the Absence of an Axial Element in Mammalian Meiotic Cells , 2001, Molecular and Cellular Biology.

[28]  R. Pearlman,et al.  Rad51 and Dmc1 Form Mixed Complexes Associated with Mouse Meiotic Chromosome Cores and Synaptonemal Complexes , 1999, The Journal of cell biology.

[29]  E. Blackburn Switching and Signaling at the Telomere , 2001, Cell.

[30]  M. Blasco,et al.  Mammalian meiotic telomeres: composition and ultrastructure in telomerase-deficient mice. , 2002, European journal of cell biology.

[31]  R. Pearlman,et al.  Synaptonemal complex proteins: occurrence, epitope mapping and chromosome disjunction. , 1994, Journal of cell science.

[32]  Harry Scherthan,et al.  Meiotic Telomere Protein Ndj1p Is Required for Meiosis-Specific Telomere Distribution, Bouquet Formation and Efficient Homologue Pairing , 2000, The Journal of cell biology.

[33]  Li Yuan,et al.  Female Germ Cell Aneuploidy and Embryo Death in Mice Lacking the Meiosis-Specific Protein SCP3 , 2002, Science.

[34]  M. Blasco,et al.  Telomere shortening in mTR−/− embryos is associated with failure to close the neural tube , 1999, The EMBO journal.

[35]  Lynda Chin,et al.  p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis , 1999, Cell.

[36]  P. Hunt,et al.  Lack of Checkpoint Control at the Metaphase/Anaphase Transition: A Mechanism of Meiotic Nondisjunction in Mammalian Females , 1997, The Journal of cell biology.

[37]  P. Hunt,et al.  To err (meiotically) is human: the genesis of human aneuploidy , 2001, Nature Reviews Genetics.

[38]  M. Matzuk,et al.  Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary. , 1999, Molecular endocrinology.

[39]  C. Tease,et al.  Analysis of Meiotic Chromosome Pairing in the Female Mouse using a Novel Minichromosome , 1998, Chromosome Research.

[40]  A. Zalensky,et al.  Telomeres in mammalian male germline cells. , 2002, International review of cytology.

[41]  C. Heyting,et al.  Centromere and telomere movements during early meiotic prophase of mouse and man are associated with the onset of chromosome pairing , 1996, The Journal of cell biology.

[42]  Paul Nurse,et al.  Fission yeast Taz1 protein is required for meiotic telomere clustering and recombination , 1998, Nature.

[43]  Kazuhiro Kikuchi,et al.  Essential Role of Fkbp6 in Male Fertility and Homologous Chromosome Pairing in Meiosis , 2003, Science.

[44]  G. Roeder,et al.  The Mnd1 Protein Forms a Complex with Hop2 To Promote Homologous Chromosome Pairing and Meiotic Double-Strand Break Repair , 2002, Molecular and Cellular Biology.

[45]  D A Agard,et al.  Evidence for the coincident initiation of homolog pairing and synapsis during the telomere-clustering (bouquet) stage of meiotic prophase. , 2000, Journal of cell science.

[46]  Robin C. Allshire,et al.  Defective meiosis in telomere-silencing mutants of Schizosaccharomyces pombe , 1998, Nature.