absence of ATM in somatic cells (9), (ii) CHK2
can be activated in an ATR-dependent manner
(10), and (iii) ATR localizes to sites of meiotic
DSBs in mice (23) prompt us to propose that the
DNA damage checkpoint pathway in mouse
oocytes involves signaling of ATR to CHK2, which
in turn signals to p53 and TAp63 (fig. S6). Additionally, spermatocytes may have a distinct DNA
damage response pathway; we did not observe
histological evidence for rescue of DSB repair-defective but synapsis-proficient spermatocytes
by deletion of Chk2 or p53 (fig. S8).
Our results are of biomedical interest with
respect to the primordial follicle pool depletion
and premature ovarian failure that can occur after cancer radiotherapy or chemotherapy. CHK2
is an attractive target because chemical inhibitors
are available, and Chk2 insufficiency is of minor
phenotypic consequence in mice (24).
References and Notes
1. F. Cole et al., Nat. Cell Biol. 14, 424–430 (2012).
2. M. Di Giacomo et al., Proc. Natl. Acad. Sci. U.S.A. 102,
3. W. J. Lu, J. Chapo, I. Roig, J. M. Abrams, Science 328,
4. N. Bhalla, A. F. Dernburg, Science 310, 1683–1686
5. P. S. Burgoyne, S. K. Mahadevaiah, J. M. Turner,
Nat. Rev. Genet. 10, 207–216 (2009).
6. M. Barchi et al., Mol. Cell. Biol. 25, 7203–7215 (2005).
7. L. G. Reinholdt, J. C. Schimenti, Chromosoma 114,
8. T. G. Baker, Mutat. Res. 11, 9–22 (1971).
9. A. Hirao et al., Mol. Cell. Biol. 22, 6521–6532
10. X. Q. Wang, J. L. Redpath, S. T. Fan, E. J. Stanbridge,
J. Cell. Physiol. 208, 613–619 (2006).
11. D. L. Pittman et al., Mol. Cell 1, 697–705 (1998).
12. X. C. Li, J. C. Schimenti, PLOS Genet. 3, e130 (2007).
13. I. Roig et al., PLOS Genet. 6, e1001062 (2010).
14. H. Niu et al., Mol. Cell 36, 393–404 (2009).
15. G. Livera et al., Reproduction 135, 3–12 (2008).
16. E. K. Suh et al., Nature 444, 624–628 (2006).
17. G. J. Seo et al., Biochem. Biophys. Res. Commun. 304,
18. X. Guo et al., Nat. Cell Biol. 11, 1451–1457
19. A. A. Mills et al., Nature 398, 708–713 (1999).
20. J. Smith, L. M. Tho, N. Xu, D. A. Gillespie, Adv. Cancer Res.
108, 73–112 (2010).
21. K. A. Cimprich, D. Cortez, Nat. Rev. Mol. Cell Biol. 9,
22. J. Lange et al., Nature 479, 237–240 (2011).
23. D. Perera et al., Mol. Biol. Cell 15, 1568–1579 (2004).
24. H. Takai et al., EMBO J. 21, 5195–5205 (2002).
Acknowledgments: This work was supported by NIH grant
GM45415 to J.C.S. and contract CO26442 from the NY State Stem
Cell Program. We thank A. Mills for providing p63 mutant mice and
M. A. Handel for critical reading of the manuscript.
Materials and Methods
Figs. S1 to S8
24 October 2013; accepted 20 December 2013
Mating Induces Shrinking and Death
in Caenorhabditis Mothers
Cheng Shi and Coleen T. Murphy*
Interactions between the germ line and the soma help optimize reproductive success. We discovered
a phenomenon linking reproductive status to longevity: In both hermaphroditic and gonochoristic
Caenorhabditis, mating leads to female shrinking and death, compressing postreproductive life span.
Male sperm induces germline- and DAF-9/DAF-12–dependent shrinking, osmotic stress susceptibility, and
subsequent life-span decrease, whereas seminal fluid induces DAF-16–dependent life-span decrease
and fat loss. Our study provides insight into the communication between males and the female germ line
and soma to regulate reproduction and longevity, revealing a high-reproduction, low–life-span state
induced by mating. Postmating somatic collapse may be an example of the sexually antagonistic influence
that males in many species exert on female behavior to maximize their own reproductive success.
Mating is an elaborately regulated process with critical individual and population consequences (1, 2). The development
of sexual mating resulted in a now ancient conflict:
Although the mother’s genome is always prop-
agated, the father is driven to maximize his ge-
nomic contribution to the exclusion of other
males, often effected through manipulation of
the mother’s behavior or physiology. This ten-
sion leads to a war between the sexes that plays
out in different ways in different species; for ex-
ample, many insects display sexual antagonism, in
which males receive benefits of mating (increased
offspring, decreased chance of female remating)
by inflicting damage on the female (3).
Reproduction and longevity are intimately
linked, with signals between the germ line and
soma coordinating the rate of aging of both tis-
sues (4–8). Reproductive aging is regulated by
Fig. 4. CHK2 signals to both p63 and p53 in oocytes. (A to E) Depletion
of primordial follicles by IR requires p53 and TAp63. Week-old ovaries were
irradiated, cultured 7 days, then immunostained. p63 and MVH are oocyte-
specific. (F) Dynamic signaling to p53 and p63 in response to meiotic and
induced DSBs. Shown are Western blots of neonatal ovarian protein. The
irradiated sample was collected 2 hours post-IR (3 Gy). Arrowhead, phosphoryl-
ated p63 (15, 16). Trip13 mutants are undergoing oocyte elimination (reflected
by MVH), hence use of more ovaries. (G to J) p53 and TAp63 are required for complete elimination of DSB repair–defective oocytes. Ovaries are 3 weeks
postpartum. (J Inset) Primordial follicles. Scale bars, 200 mm.
Lewis-Sigler Institute for Integrative Genomics and Department
of Molecular Biology, Princeton University, Princeton, NJ 08544,
*Corresponding author. E-mail: firstname.lastname@example.org