Uterine dysfunction and genetic modifiers in centromere protein B-deficient mice

Centromere protein B (CENP-B) binds constitutively to mammalian centromere repeat DNA and is highly conserved between humans and mouse. Cenpb null mic e appear normal but have lower body and testis weights. We demonstrate here that testis-weight I eduction is seen in male null mice generated on three different genetic backgrounds (denoted R1, W9.5, and Cn), whereas body-wei ght reduction is dependent on the genetic background as well as the gender of the animals. In addition, Cenpb null females show 31%, 33%, and 44% redu ced uterine weights on the RI, W9.5, and C57 backgrounds, respectively. Pro duction of "revertant" mice lacking the targeted frameshift mutation but no t the other components of the targeting construct corrected these differenc es, indicating that the observed phenotype is attributable to Cenpb gene di sruption rather than a neighbouring gene effect induced by the targeting co nstruct. The R1 and W9.5 Cenpb null Females are reproductively competent bu t show age-dependent reproductive deterioration leading to a complete break down at or before 9 months of age. Reproductive dysfunction is much more se vere in the C57 background as Cenpb null females are totally incompetent or are capable of producing no more than one litter. These results implicate a further genetic modifier effect on female reproductive performance. Histo logy of the uterus reveals normal myometrium and endometrium but grossly di srupted luminal and glandular epithelium. Tissue in situ hybridization demo nstrates high Cenpb expression in the uterine epithelium of wild-type anima ls. This study details the first significant phenotype of Cenpb gene disrup tion and suggests an important role of Cenpb in uterine morphogenesis and f unction that may have direct implications for human reproductive pathology.