SUMO-1, human male germ cell development, and the androgen receptor in the testis of men with normal and abnormal spermatogenesis

Abstract

Vigodner, Margarita, Tomomoto Ishikawa, Peter N. Schlegel, and Patricia L. Morris. SUMO-1, human male germ cell development, and the androgen receptor in the testis of men with normal and abnormal spermatogenesis. Am J Physiol Endocrinol Metab 290: E1022-E1033, 2006. First published December 13, 2005 doi:10.1152/ajpendo.00527.2005.-Sumoylation affects multiple cellular events, including chromatin inactivation and transcriptional repression. Our data provide the first characterization of small ubiquitin-related modifier-1 (SUMO-1) expression during human spermatogenesis by the use of high-resolution cellular SUMO-1 bioimaging. During human meiotic prophase, SUMO-1 localizes to sex chromosomes and centromeric and pericentromeric chromatin. As human spermatocytes progress toward the end of prophase in meiosis I, SUMO-1 is no longer detected within the sex body and pericentromeric heterochromatin but localizes exclusively to centromeres. SUMO-1 localization along sex chromosome axes, pseudoautosomal region, and centromeres of both chromosomes supports a role for SUMO-1 sumoylation in epigenetic events occurring over the entire sex body, e.g., meiotic sex chromosome inactivation and chromatin condensation. Centromeric SUMO-1 throughout meiotic prophase suggests a role in centromeric chromatin condensation and/or other centromere/kinetochore functions. SUMO-1 is likely involved in both facultative and constitutive heterochromatin processes in spermatocytes. Haploid round spermatids show a consistent association of SUMO-1 with centromeric clusters. During spermatid elongation, SUMO-1 localizes in the manchette perinuclear ring. Steroidogenic Leydig cells show some cytoplasmic but strong nuclear and perinuclear SUMO-1. Peritubular myoepithelial cell SUMO-1 colocalizes with centromeric heterochromatin. In epithelial Sertoli cells, when associated with centromeric heterochromatin, SUMO-1 is adjacent but not colocalized with the nucleolus. Male germ cells demonstrate no SUMO-1 nucleolar association. Human and rodent Sertoli cells consistently show an inverse correlation between androgen receptor (AR) and SUMO-1 expression and compartmentalization. Sertoli cells from certain infertile patients, however, showed greatly decreased SUMO-1 and AR. Our data suggest that human testicular SUMO-1 has specific functions in heterochromatin organization, meiotic centromere function, and gene expression.small ubiquitin-related modifier-1; meiosis; chromatin; centromere; spermatids; Sertoli cells; Sertoli cell-only; maturational arrest; infertility THE SMALL UBIQUITIN-RELATED MODIFIER 1 (SUMO-1) is a member of a family of ubiquitin-related proteins. In contrast to the process of ubiquitination, which is largely but not always associated with proteolytic pathways, sumoylation is instead implicated in cellular events such as protein-protein interactions, nuclear-cytoplasmic transport, and the formation of specific nuclear heterochromatin domains. Thus sumoylation participates in the regulation of transcription and DNA replication and repa...

Sumoylation dynamics during keratinocyte differentiation

“…Recent studies on myoblast differentiation (Riquelme et al, 2006), embryonic development (Yamaguchi et al, 2005), genital tissue maturation (Vigodner et al, 2006) and synaptic formation (Shalizi et al, 2006) highlight sumoylation not only as a modifier of individual proteins but also as a global regulator of cellular development. In the present study, we investigated the role of sumoylation in another complex process, keratinocyte differentiation.…”

“…Several recent studies in metazoan systems support such a role for sumoylation in aspects of development and differentiation. Sumoylation is required for correct vulvar development in C. elegans (Leight et al, 2005;Poulin et al, 2005), is implicated in male germ cell maturation (Vigodner et al, 2006) and promotes differentiation of postsynaptic dendrites (Shalizi et al, 2006). Sumoylation is also critical for maintaining nuclear structure and chromosomal segregation during blastocyst development, with the absence of Ubc9 leading to an embryonic lethal phenotype (Nacerddine et al, 2005).…”

SUMO proteins are involved in the stress response during spermatogenesis and are localized to DNA double-strand breaks in germ cells

“…These differences can cause differently interpreted results. For example, the first localization study in humans detected SUMO on the sex chromosomes of some meiotic spermatocytes, and another study argued such localization (Vigodner et al 2006, Metzler-Guillemain et al 2008. However, the last study failed to detect any signal along synaptonemal complexes in pachytene spermatocytes, while another group demonstrated such localization and suggested synaptonemal complex proteins as possible sumoylated targets (Brown et al 2008, Metzler-Guillemain et al 2008.…”

“…The exact model of how SUMO regulates these functions is largely unknown. SUMO1 and SUMO2/3 have been recently studied during mouse and human spermatogenesis, where they were localized to different subdomains of germ and somatic testicular cells (Rogers et al 2004, Vigodner & Morris 2005, Vigodner et al 2006, Brown et al 2008, Metzler-Guillemain et al 2008, Vigodner 2009 expression patterns of genes related to the sumoylation pathway in different germ cell populations, but little is still known about the regulation of spermatogenesis by sumoylation (La Salle et al 2008). The localization pattern of SUMO1 and SUMO2/3 in the testis appeared not to be fully overlapping, although a recent study using SUMO1 knockout mice does not support differential roles of the SUMO isoforms during spermatogenesis .…”

SUMO1 in human sperm: new targets, role in motility and morphology and relationship with DNA damage

“…Although extensively studied in somatic cells, little is known about protein sumoylation in testicular functions and mature sperm (Vigodner 2011). SUMO1 has been found in mouse and rat testis , La Salle et al 2008 in all stages of the process of spermatogenesis, and in specific chromatin and other cellular domains both in germ and somatic cells of human testis (Vigodner et al 2006), but its role during spermatogenesis remains elusive. Recently, modifications in the levels of SUMO1 and SUMO2/3 have been detected in mouse germ cells following exposure to oxidative and heat stress (Shrivastava et al 2010), suggesting a role in responses to stress, as described for somatic cells (Comerford et al 2003, Manza et al 2004.…”