Title Cytokines and Junction Restructuring During Spermatogenesis

CORE Metadata, citation and similar papers at core.ac.uk Provided by HKU Scholars Hub Cytokines and junction restructuring during spermatogenesis - Title A lesson to learn from the testis Author(s) Xia, W; Mruk, DD; Lee, WM; Cheng, CY Cytokine And Growth Factor Reviews, 2005, v. 16 n. 4-5, p. 469- Citation 493 Issued Date 2005 URL http://hdl.handle.net/10722/84892 Rights Cytokine & Growth Factor Reviews. Copyright © Elsevier Ltd. DTD 5 This is a pre-published version Cytokine & Growth Factor Reviews xxx (2005) xxx–xxx 1 www.elsevier.com/locate/cytogfr 2 Cytokines and junction restructuring during spermatogenesis—a lesson 3 to learn from the testis 4 Weiliang Xia, Dolores D. Mruk, Will M. Lee, C. Yan Cheng * 5 Population Council, Center for Biomedical Research, 1230 York Avenue, New York, NY 10021, USA 6 87 9 Abstract 10 In the mammalian testis, preleptotene and leptotene spermatocytes residing in the basal compartment of the seminiferous epithelium must 11 traverse the blood-testis barrier (BTB) during spermatogenesis, entering the adluminal compartment for further development. However, until 12 recently the regulatory mechanisms that regulate BTB dynamics remained largely unknown. We provide a critical review regarding the 13 significance of cytokines in regulating the ‘opening’ and ‘closing’ of the BTB. We also discuss how cytokines may be working in concert with 14 adaptors that selectively govern the downstream signaling pathways. This process, in turn, regulates the dynamics of either Sertoli–Sertoli 15 tight junction (TJ), Sertoli–germ cell adherens junction (AJ), or both junction types in the epithelium, thereby permitting TJ opening without 16 compromising AJs, and vice versa. We also discuss how adaptors alter their protein–protein association with the integral membrane proteins at 17 the cell–cell interface via changes in their phosphorylation status, thereby altering adhesion function at AJ. These findings illustrate that the 18 testis is a novel in vivo model to study the biology of junction restructuring. Furthermore, a molecular model is presented regarding how 19 cytokines selectively regulate TJ/AJ restructuring in the epithelium during spermatogenesis. 20 # 2005 Published by Elsevier Ltd. 21 Keywords: Spermatogenesis; Testis; Junction restructuring; Cytokines; TGF-b3; TNFa; p38 MAPK; ERK; JNK; Blood-testis barrier; Adherens junction; 22 Tight junction; Adaptors; Ectoplasmic specialization 24 23 25 1. Introduction Spermatogenesis can be divided into three distinct phases 41 which provide an upward of 150 Â 106 spermatozoa per 42 26 The production of mature spermatozoa (haploid, 1n)from day per man [1,3]. The germline stem cells spermatogonia 43 27 spermatogonia (diploid, 2n) is essential for the perpetuation of can either self-proliferate (phase 1) or differentiate into 44 28 all mammalian species. Such event, known as spermatogen- primary spermatocytes, which then undergo meiosis and 45 29 esis in the male, takes places in the functional unit of the testis differentiate into secondary spermatocytes and eventually 46 30 called the seminiferous tubule. Seminiferous tubules, in turn, haploid spermatids (phase 2). These cells, in turn, 47 31 coordinate with Leydig cells in the interstitium and the brain differentiate morphologically and functionally to sperma- 48 32 via the hypothalamic-pituitary-testicular axis to regulate tozoa via spermiogenesis (phase 3), which are released into 49 33 spermatogenesis [1,2]. Although spermatogenesis varies in the tubule lumen at spermiation [1,3]. This entire process of 50 34 detail in different species (e.g., minks are seasonal breeders germ cell development in the seminiferous epithelium is 51 35 exhibiting seasonally or environmentally responsive phases in dependent on temporal and spatial expression of unique sets 52 36 this process whereas spermatogenesis continues throughout of genes and proteins. In the rat testis, an epithelial cycle 53 37 the entire life span in humans and rodents), the cellular (12–14 days duration) can be divided into 14 stages which 54 38 constituents and the basic physiology of the testes are rather are classified according to the unique germ cell types that 55 39 similar [3]. We limit our discussion largely in rats, mice and/or associate with Sertoli cells in the epithelium [3,4]. It takes 56 40 men since most studies were conducted in these species. 58 days for a single spermatogonium to fully differentiate 57 41 and develop into 256 spermatozoa. As such, it takes 4.5 58 epithelial cycles for one spermatogonium to differentiate 59 * Corresponding author. Tel.: +1 212 327 8738; fax: +1 212 327 8733. into 256 spermatids. For each stage, at least four germ cell 60 E-mail address: [email protected] (C.Y. Cheng). types are present in the epithelium that are organized 61 1359-6101/$ – see front matter # 2005 Published by Elsevier Ltd. doi:10.1016/j.cytogfr.2005.05.007 UNCORRECTED PROOF CGFR 365 1–24 DTD 5 2 W. Xia et al. / Cytokine & Growth Factor Reviews xxx (2005) xxx–xxx Fig. 1. Spermatogenesis and cell junctions in the seminiferous epithelium of the mammalian testis (e.g. rats). (A) This is the cross-section of a seminiferous tubule from an adult rat testis showing the intimate relationship between Sertoli cells (N, Sertoli cell nucleus) and germ cells (e.g., pachytene spermatocyte PS, round spermatid RS). (B) Schematic drawing of developing germ cells and their intimate relationship with Sertoli cells during spermatogenesis in the seminiferous epithelium. Also shown is the relative location of different junction types in the epithelium between Sertoli cells as well as between Sertoli and germ cells. Sertoli and germ cells constitue the seminiferous epithelium that is adjacent to the tunica propria. Differentiating germ cells must migrate from the basal to the adluminal compartment, traversing the BTB, which has physically divided the epithelium into the basal and adluminal compartment. (C–E) Electron micrographs of cross sections of seminiferous epithelium illustrating the ultrastructural features of the blood-testis barrier at low (C) and high (D) magnification. The basal ES is characterized by the presence of actin filament bundles (white arrows) sandwiched between the cisternae of endoplasmic reticulum (er), and the UNCORRECTED PROOF CGFR 365 1–24 DTD 5 W. Xia et al. / Cytokine & Growth Factor Reviews xxx (2005) xxx–xxx 3 62 spatially into layers from the base to the lumen of the cell extending from the base to the apex of the seminiferous 106 63 seminiferous tubule [3,4]. Furthermore, spermatogenesis tubule [3]. It is physically reshaped by germ cells to possess 107 64 cannot completewithout the support of Sertoli cells, which are many cytoplasic processes because each Sertoli cell is 108 65 the only other cell type in the seminiferous epithelium behind ‘nursing’ about 30–50 germ cells at different stages of their 109 66 the BTB besides germ cells (note: the BTB has physically development at any given time during the epithelial cycle 110 67 divided the epithelium into the basal and adluminal [13,14]. In the rat, Sertoli cells cease to proliferate at about 111 68 compartment, see Fig. 1) [5–7]. Except for the spermatogonia, day 20 postnatal and the number of these nursing cells 112 69 developing germ cells move progressively toward the lumen determines how many germ cells can be supported and 113 70 [8]. For instance, preleptotene and leptotene spermatocytes produced via spermatogenesis in the testis [3], illustrating 114 71 that lie at the periphery of the tubule and outside the BTB must the crucial function of Sertoli cells. For instance, Sertoli 115 72 traverse the BTB at late stages VIII and early IX of the cells provide structural support for germ cells and their 116 73 epithelial cycle [8]. translocation, create the BTB and define the polarity of the 117 74 It is conceivable that enormous Sertoli–germ cell epithelium, secrete numerous biological factors and 118 75 interactions take place in the seminiferous epithelium nutrients for germ cells, and conduct other vital functions 119 76 throughout spermatogenesis [1–4,6,9,10]. If one views pertinent to spermatogenesis (e.g., phagocytosis) [2,3,14]. 120 77 spermatogenesis as a voyage of a germ cell that moves from 78 the basal to the adluminal compartment while developing to a 2.2. Sertoli–Sertoli and Sertoli–germ cell junctions 121 79 mature spermatozoon, this process involves numerous 80 decision makings and executions. It also requires signalings The different junction types that are found in the 122 81 in and out of germ cells to facilitate this event. Although it is seminiferous epithelium have recently been reviewed [1,2]. 123 82 not entirely clear regarding the sequence of these signals, Similar to other epithelia or endothelia, virtually all major 124 83 there are at least two sources: external signals from outside the junction types are found in the testis. Besides the tight 125 84 tubule (e.g., via Leydig cells, peritubular myoid cells, and junctions that are restricted to the BTB, several anchoring 126 85 both paracrine and hormonal factors including those from the junction types (four are found in most epithelia) are also 127 86 pituitary gland), and internal crosstalks between germ and detected in the testis: (a) adherens junction (including basal 128 87 Sertoli cells (e.g., integrin-mediated signalings) [5,6,11,12]. and apical ectoplasmic specialization [ES], basal and apical 129 88 The phenotypic consequence of these signalings is mani- tubulobulbar complex [TBC]); (b) desmosome-like junctions; 130 89 fested, at least in part, via the constant remodeling at the and (c) hemidesmosomes (for reviews, see [1,2,10,15]). ES is 131 90 Sertoli–Sertoli and Sertoli–germ cell interfacewhere different a testis-specific, actin-based adherens junction localized at 132 91 cell junction types are present [1,2]. two sites in the seminiferous epithelium: basal and apical 133 92 The identities of these signals and the details of the compartment (see Fig.

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