Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

The Serine/Theonine Kinase 35 (Stk35) allele locus is required for normal fertility (#101)

Kate Loveland 1 2 , Yoichi Miyamoto 1 , Penny Whiley 1 , Hoey Goh 1 , Chin Wong 1 , Gavin Higgins 1 , Diana Hansen 3 , Lynne Mayne 1 , Paul McMenamin 2
  1. Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
  2. Anatomy and Cell Biology, Monash University, Clayton, Vic, Australia
  3. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

The importin a family of proteins are key mediators of nucleocytoplasmic transport, and much of our ongoing work has addressed their regulation and functions during mammalian spermatogenesis.  Although they are predominantly cytoplasmic, we identified importin as as uniquely nuclear-localized in meiotic and haploid male germ cells, and have sought to understand why. Importin as are also nuclear-localized in HeLa cells exposed to hydrogen peroxide, and we recently identified STK35 as a uniquely up-regulated target of nuclear importin α2 and α4 proteins [1].  Serine/threonine kinase 35 (STK35) was identified as CLP36-interacting kinase 1 (Clik1) with autophosphorylation activity, exhibiting highest tissue transcript levels in human testes [2] and upregulation in certain cancers [3]. STK35 protein was shown to interact with nuclear actin, and it has been implicated in cell cycle maintenance and endothelial cell migration. We recently identified the presence of a lncRNA arising from the same locus (see Whiley et al, SRB 2014).  Our in situ hybridization analysis identified Stk35 transcript isoforms in different male germ cell types. We developed an Stk35 knockout (KO) mouse, with the genetic deletion encompassing both the coding and non-coding RNAs. Viable KO mice were infrequent in both sexes, and those surviving had lower testis and ovary weights, and both male and female gonads were germ cell-deficient.  A remarkable range of eye defects was observed, spanning from developmental arrest to impaired iridocorneal angle development. In situ hybridization confirmed the localization of Stk35 transcripts to discrete cell types within each organ.  These findings demonstrate that the genomic region encoding the Stk35 allele contributes to normal germ cell and eye development, suggesting that a key function of importin a proteins is to regulate its activity. Ongoing studies address Stk35 function in malaria susceptibility and cancers, building on clues from its identification in disease contexts.

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