Novel Importin-α Family Member Kpna7 Is Required for Normal Fertility and Fecundity in the Mouse*

Abstract

Nuclear importing system and nuclear factors play important roles in mediating nuclear reprogramming and zygotic gene activation. However, the components and mechanisms that mediate nuclearly specific targeting of the nuclear proteins during nuclear reprogramming and zygotic gene activation remain largely unknown. Here, we identified a novel member of the importin-␣ family, AW146299(KPNA7), which is predominantly expressed in mouse oocytes and zygotes and localizes to the nucleus or spindle. Mutation of Kpna7 gene caused reproductivity reduction and sex imbalance by inducing preferential fetal lethality in females. Parthenogenesis analysis showed that the cell cycle of activated one-cell embryos is loss of control and ahead of schedule but finally failed to develop into blastocyst stage. Further RT-PCR and epigenetic modification analysis showed that knocking out of Kpna7 induced abnormalities of gene expression (dppa2, dppa4, and piwil2) and epigenetic modifications (down-regulation of histone H3K27me3). Biochemical analysis showed that KPNA7 interacts with KPNB1 (importin-␤1). In summary, we identified a novel Kpna7 gene that is required for normal fertility and fecundity.

Crucial Genes and Pathways in Chicken Germ Stem Cell Differentiation

“…A recent study identified the PRDM14 expression by microarray assay, in particular, undifferentiated human ESCs (14), and Chia et al (15) described it as an important transcription factor in human pluripotency maintenance. HU stated that PLK1, a polo-like kinase family member, was involved in cell mitosis and also expressed in a high significant manner in many of human malignancies so it is considered a carcinogenic gene (16).…”

Changing expression and subcellular distribution of karyopherins during murine oogenesis

“…Emerging evidence, including phenotypes of KPNA knockout mouse models, suggests there may be a corresponding role for this protein family in the female germline. KPNA7 is expressed in oocytes and appears to be important for pre-implantation development with parthogenetically activated eggs from conditional mutants failing to develop to the blastocyst stage (Hu et al 2010). The absence of KPNA1, also known as importin a5, leads to reduced numbers of growing follicles and hypoplasia of the reproductive tract in mice (Moriyama et al 2011).…”

Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation

“…27,28 In mice, truncating mutations resulted in reduced reproductive potential and female lethality. 25 These expression patterns are interesting as one of our subjects had ambiguous genital findings both at birth and on subsequent examination, without identifiable endocrine disturbance. The family member KPNA2 is a binding partner of the androgen receptorinteracting protein 3 (Arip3).…”

“…In the mouse KPNA7 may interact with KPNB1. 25 Mutations in the nuclear localization sequence of ARX are associated with both infantile spasms and lissencephaly, and result in abnormal subcellular distribution of the protein product. 26 As loss-of-function mutations in ARX cause a spectrum of infant-onset epilepsy disorders, this observation further supports the concept that nuclear concentrations of ARX proteins might be compromised by reduced activity of the import machinery.…”