Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Importin proteins: central and essential roles in spermatogenesis (#109)

Kate Loveland 1 2 , Yoichi Miyamoto 3 , Penny A.F. Whiley 1 , Julia Young 1 2 , David Jans 4 , Yoshihiro Yoneda 3 5
  1. Hudson Institute of Medical Research, Clayton, Victoria, Australia
  2. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
  3. Health and Nutrition, National Institutes of Biomedical Innovation, Osaka, Japan
  4. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC
  5. National Institutes of Biomedical Innovation, Osaka, Japan

Importin (IMP) proteins mediate regulated nucleocytoplasmic transport and are therefore central to controlling gene expression and developmental events.  We originally proposed that coordinated expression of an IMP and a cell-specific transcription factor would drive a developmental switch by enabling transcription factors and other nuclear proteins to enter the nucleus appropriately.  In exploring their production and roles in mammalian gametogenesis, we identified tight regulation of IMPaand b mRNAs and proteins throughout spermatogenesis and made the remarkable observation that certain IMPs are nuclear-localized in meiotic and haploid male germ cells.  IMPa-specificbinding partners differ between spermatocytes and spermatids; many are cytoplasmic proteins and several are essential for male fertility.  IMPs localization to distinct regions in mature mouse sperm highlights their potential to serve as adaptors for protein trafficking to non-nuclear sites. IMPa2 can also mediate cytoplasmic protein retention, and we identified a new putative cytoplasmic retention motif in two IMPa2-binding proteins, Senataxin and Smarca4 (Brg1).  In exploring the role of nuclear-localized importins, we identified STK35 as important transcriptional target for nuclear-localized IMPas that is highly expressed in the testis. Because cellular stressors such as hydrogen peroxide cause IMPas nuclear sequestration, we examined whether nuclear IMPas influence germ cell stress responses.  Examining two unique mouse models revealed that levels of IMPa4 in spermatids determines their survival in oxidative stress conditions.  The STK35 allele encodes both coding and non-coding RNAs which are coordinately regulated during spermatogenesis and differentially regulated by oxidative stress.  STK35 KO male mice are completely sterile due specifically to loss of germ cells. Germ cell-specific deletion of the IMPb IPO5 also causes male-sterility.  Thus, our interrogation of IMPs in spermatogenesis has revealed new genes required for male fertility and revealed a plethora of mechanisms by which importin proteins can modify cellular fate.