PgmNr M5072: Mice mutant for Cecr2, which codes for a chromatin remodelling protein, show severe male subfertility that significantly improves with age.

Authors:
Heather E. McDermid; Chelsey B. Weatherill; Kenji Rowel Lim; Vivian V. Nguyen; Ross C. Humphreys; Kacie A. Norton


Institutes
University of Alberta, Edmonton, AB, Canada.


Abstract:

Mammalian reproduction requires an exquisitely complex interplay of genes which must be regulated spatially and temporally to ensure both development of the gonad and successful fertilization of gametes. Part of this process depends on chromatin remodellers, which are able to affect nuclear processes such as gene transcription, DNA replication, recombination or repair through modulation of chromatin structure. Mutations in chromatin remodelling gene Cecr2, which is expressed in spermatogonial cells, result in an unusual form of male subfertility that is most severe at maturity and improves with age. This improvement is demonstrated by three different measures. First, mutant males (BALB/c-Cecr2Gt(pGT1)Hemc/Cecr2Gt(pGT1)Hemc) are least fertile immediately after sexual maturity (42-60 days). Within 2 months, litter sizes improve from 11.7% to 58.3% of the litter sizes of their wildtype brothers. Second, histological analysis reveals severe defects in the seminiferous tubules of newly mature males, including tubules that have very few cell layers and are not completing spermatogenesis. These defects become less prevalent and less severe with age, until testes at 3+ months appear close to normal in structure. Histological analysis of immature testes shows that mutant testes at 14 days are indistinguishable from wild type, and defects are first visible at between 19 and 21 days. Third, analysis of wildtype eggs, fertilized in vivo and collected 5 hours later, indicate that subfertility in mutants is due to fewer oocytes being fertilized. Mutants males aged 42-60 days show a fertilization rate of ~5% compared to their wild type brothers. At 60-100 days of age the mutant males show ~35% of the normal fertilization rate, and after 100 days the fertilization rate is not significantly different between mutants and wild types. Intriguingly, this partial rescue of the age dependent phenotype may be due to increasing levels of Cecr2 transcript within the mutant testis, either from the previously characterized Cecr2 transcript with a hypomorphic mutation, or from a novel transcript expressed from a newly discovered alternate exon 1. Determining how Cecr2 causes subfertility in mice and the mechanism by which the phenotype improves with age will advance our understanding of the various roles that chromatin remodeling plays during spermatogenesis and fertilization.