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Clues to Regulation of Spermatogenic Development☆ View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1813 (2011) 1668–1688 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Expression of nucleocytoplasmic transport machinery: Clues to regulation of spermatogenic development☆ Andrew T. Major a,c, Penny A.F. Whiley b,c, Kate L. Loveland a,b,c,⁎ a Department of Anatomy and Developmental Biology, Monash University, Australia b Department of Biochemistry and Molecular Biology, Monash University, Australia c The ARC Centre of Excellence in Biotechnology and Development, Australia article info abstract Article history: Spermatogenesis is one example of a developmental process which requires tight control of gene expression Received 27 August 2010 to achieve normal growth and sustain function. This review is based on the principle that events in Received in revised form 22 February 2011 spermatogenesis are controlled by changes in the distribution of proteins between the nuclear and Accepted 11 March 2011 cytoplasmic compartments. Through analysis of the regulated production of nucleocytoplasmic transport Available online 17 March 2011 machinery in mammalian spermatogenesis, this review addresses the concept that access to the nucleus is tightly controlled to enable and prevent differentiation. A broad review of nuclear transport components is Keywords: Spermatogenesis presented, outlining the different categories of machinery required for import, export and non-nuclear Testis functions. In addition, the complexity of nomenclature is addressed by the provision of a concise yet Importin comprehensive listing of information that will aid in comparative studies of different transport proteins and Exportin the genes which encode them. We review a suite of existing transcriptional analyses which identify common Karyopherin and distinct patterns of transport machinery expression, showing how these can be linked with key events in Nuclear transport spermatogenic development. The additional importance of this for human fertility is considered, in light of data that identify which importin and nuclear transport machinery components are present in testicular cancer specimens, while also providing an indication of how their presence (and absence) may be considered as potential mediators of oncogenesis. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import. © 2011 Published by Elsevier B.V. 1. Introduction: Nucleocytoplasmic transport in the context affect transcription or perform other nuclear functions, they must of spermatogenesis utilise importin-mediated nuclear import pathways. This review examines the machinery that controls nucleocyto- 1.1. What is an importin/exportin? plasmic transport in the context of mammalian spermatogenesis. Spermatogenesis is the process by which mature spermatozoa form Central to nucleocytoplasmic transport are the karyopherin family of from spermatogonial stem cells within the testis. Its successful proteins. These ferry cargoes in and out of the eukaryotic cell nucleus completion is dependent on successive division and differentiation and consists of two fundamentally distinct groups, karyopherin αsand steps which require many changes in gene expression; these are karyopherin βs [3–6]. Further categorisation reflects their functions in coordinated by a plethora of transcription and other factors expressed nuclear import (termed importins) and export (exportins). Because the in the testis [1,2]. For these proteins to access the nucleus, and thereby karyopherin αs are all importins, they are often termed importin αs, and the two terms may be used interchangeably. In contrast, the karyopherin βs have roles in nuclear import and export, and this functional distinction usually forms the basis for naming them as Abbreviations: NE, Nuclear envelope; NPC, Nuclear pore complex; NUPs, Nucleo- importin βs and exportins, respectively [3–5]. This separation may be porins; NLS, Nuclear localisation signal; cNLS, Classical nuclear localisation signal; NES, β Nuclear export signal; IBB, Importin beta binding; RAN-GTP, RAN, in its GTP bound inappropriate, as certain karyopherin s are now understood to bind form; RAN-GDP, RAN, in its GDP bound form; SEM, Standard error of the mean; GEO, distinct cargo sets for both import and export [3,7,8]. Gene expression omnibus; TGFβ, Transforming growth factor beta; miRNAs, Micro Each of the more than twenty karyopherin proteins encoded within RNAs; SRY, Sex determining region on the Y chromosome; LMB, Leptomycin B the mouse and human genomes binds a different subset of cargo proteins ☆ This article is part of a Special Issue entitled: Regulation of Signaling and Cellular which contain nuclear localisation signal(s) (NLS) or nuclear export Fate through Modulation of Nuclear Protein Import. ⁎ Corresponding author at: Building 77, Wellington Road, Monash University, signal(s) (NES) [9,10]. Some cargoes can be transported by several Clayton, Victoria, Australia 3800, Tel.: +61 3 99029337 Fax: +61 3 99029500. karyopherins, while others appear to require one specifickaryopherinfor 0167-4889/$ – see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.bbamcr.2011.03.008 A.T. Major et al. / Biochimica et Biophysica Acta 1813 (2011) 1668–1688 1669 nuclear import or export. Regulated nuclear transport of key factors can facilitated and is typically mediated by a transport carrier (e.g. dramatically affect signalling outcomes and cell fate [11],consistentwith karyopherin). The NPC is comprised of around 30 different nucleo- the concept that the progressive increase in karyopherin numbers with porins (NUPs). Some NUPs contribute to the eight spoke symmetry of evolutionary complexity may enable greater diversity in signalling the NPC nuclear “basket” structure and to the filaments extending into outcomes, required for complex organ development [6,12]. the cytoplasm (Fig. 1) [21]. The FG-NUPs which localise along the inner surfaces of the NPC channel feature hydrophobic repeat 1.2. The contribution of regulated nuclear transport to development sequences, termed FG-repeats, which fill the channel [22]. These FG- NUPs form the barrier that blocks the passage of larger molecules and An early demonstration that regulated importin expression simultaneously provide binding sites for the proteins that mediate controls nuclear protein access and thereby mediates changes in active nuclear transport [22]. function relates to the Drosophila heat shock transcription factor Facilitated transport into the nucleus by importins requires a (HSF). In the early Drosophila embryo, HSF is abundant, but it is unable nuclear localisation signal (NLS) on the cargo protein. The principal to enter the nucleus and the embryo has no heat shock response [13]. feature of the classical NLS (cNLS) is a single stretch of basic amino This has been suggested to enable rapid growth even in the presence acids (monopartite cNLS) or two closely spaced stretches of basic of an environmental insult during early embryogenesis, and after amino acids (bipartite cNLS)[3]). These cNLSs are recognised by cycle 13 the synthesis of the Drosophila homologue of Kpna4 (an importin α(s), while the NLSs that importin β(s) recognise contain importin α) delivers HSF to the nucleus and the heat shock response is much greater variation [10,23,24]. Cargoes of exportin 1 (XPO1) subsequently acquired [13]. contain a nuclear export signal (NES) consisting of hydrophobic Thus, the core concept examined in this review is that to trigger residues, predominantly leucine [25], while different exportins the appropriate developmental changes throughout spermatogenesis, mediate nuclear export in a similar manner (discussed further in correct spatiotemporal production of both nuclear factors and Section 2.4) but may also recognise and export cargoes that do not appropriate importins/exportins is required [14,15]. It builds on contain this motif [26–30]. previous knowledge that importin α family members are differen- tially expressed in certain developmental processes and in specific 2.2. Nuclear import tissue types [16,17], particularly within the testis and brain [16]. This review describes what is currently known about expression of In general terms, active nuclear import is mediated in two different karyopherins and other nucleocytoplasmic transport machinery in ways by importins. During importin β-mediated nuclear import relation to functional changes required through the progressive (Fig. 1A), the NLS-containing cargo forms a transport complex when it events of spermatogenesis in humans and mice. binds importin β in the cytoplasm. Transient interactions between importin β and FG-NUPs mediate NPC docking and translocation of 1.3. The karyopherin calamity: a table of clarity the complex into the nucleus [22,31]. Within the nucleus, the guanine nucleotide binding protein RAN in its GTP bound form (RAN-GTP) The large number of karyopherins identified within the mouse and binds to importin β [4], dissociating the complex and releasing the human genomes, variations in assigned gene names and differences in cargo to perform nuclear action(s) (discussed further in Section 2.4) the number of genes present between these and other species all have [32]. led to some uncertainty regarding to which karyopherin(s) individual In contrast to the importin βs which mediate
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