The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency

Abstract

Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. Here, we show that in mice of the 129Sv strain, loss of Dmrt1 causes a high incidence of teratomas, whereas these tumors do not form in Dmrt1 mutant C57BL/6J mice. Conditional gene targeting indicates that Dmrt1 is required in fetal germ cells but not in Sertoli cells to prevent teratoma formation. Mutant 129Sv germ cells undergo apparently normal differentiation up to embryonic day 13.5 (E13.5), but some cells fail to arrest mitosis and ectopically express pluripotency markers. Expression analysis and chromatin immunoprecipitation identified DMRT1 target genes, whose missexpression may underlie teratoma formation. DMRT1 indirectly activates the GDNF coreceptor Ret, and it directly represses the pluripotency regulator Sox2. Analysis of human germ cell tumors reveals similar gene expression changes correlated to DMRT1 levels. Dmrt1 behaves genetically as a dose-sensitive tumor suppressor gene in 129Sv mice, and natural variation in Dmrt1 activity can confer teratoma susceptibility. This work reveals a genetic link between testicular dysgenesis, pluripotency regulation, and teratoma susceptibility that is highly sensitive to genetic background and to gene dosage.GDNF ͉ testicular teratoma ͉ germ cell tumor ͉ embryonal carcinoma

Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line

“…Since Sox2, which forms a heterodimeric complex with Oct4, has been shown to be a key player in the pluripotency of ES cells [4], Sox2 expression in the germ cell line may lead to the reacquisition of potential pluripotency in this lineage. Indeed, it has been proposed that testicular teratoma susceptibility might be linked to the lack of Sox2 repression by DMRT1 in prospermatogonia [44]. In agreement with this hypothesis, we never succeeded in obtaining EG colonies from Sox2 loxP/lacz -Blimp Cre embryos.…”

DM Domain Genes: Sexual and Somatic Development During Vertebrate Embryogenesis

“…From this data, it was clear that Dmrt1 is a critical regulator of testis development in the mouse. While Zarkower's group was later mostly concentrated on mouse functional studies providing more and more interesting data about the role of DMRT1 in mammalian sexdevelopmental pathways (Fahrioglu et al, 2007;Kim et al, 2007a;Krentz et al, 2009;Matson et al, 2010;Murphy et al, 2010;Krentz et al, 2011;Matson et al, 2011), Sinclair and his coworkers were focused on studies in the chicken (Smith et al, 1999b;Smith at al., 2003). They were constantly looking for strong evidence for Dmrt1 as a male dosage-sensitive sexdetermination locus, previously shown to be linked to the Z chromosome (avian males are www.intechopen.com homogametic ZZ) in the region highly homologous to human 9 chromosome bearing the DMRT1 locus (Nanda et al, 1999;Nanda et al, 2000).…”

“…Furthermore, male Dmrt1 knockout mice were found to have postnatal affected testes but were not sex reversed . Murine Dmrt1, however, through its expression in premeiotic germ cells and in Sertoli cells of both foetal and postnatal gonads, controls many aspects of testicular development, including differentiation, proliferation, migration and pluripotency of germ cells as well as proliferation and differentiation of Sertoli cells (Fahrioglu et al, 2007;Kim et al, 2007;Krentz et al, 2009). …”

Dmrt1 mutation causes a male-to-female sex reversal after the sex determination by Dmy in the medaka

“…Dmrt1 is expressed and required for both the germ cells and the Sertoli cells of the testes (Kim et al 2007;Krentz et al 2009;Matson et al 2010). XY Dmrt1-null mutant mice are born as males with testes, but these gonads later undergo abnormal differentiation (Raymond et al 2000).…”