Cell type-autonomous and non-autonomous requirements for Dmrt1 in postnatal testis differentiation

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Developmental Biology (Impact Factor: 3.64). 08/2007; 307(2):314-27. DOI: 10.1016/j.ydbio.2007.04.046
Source: PubMed

ABSTRACT Genes containing the DM domain, a conserved DNA binding motif first found in Doublesex of Drosophila and mab-3 of Caenorhabditis elegans, regulate sexual differentiation in multiple phyla. The DM domain gene Dmrt1 is essential for testicular differentiation in vertebrates. In the mouse, Dmrt1 is expressed in pre-meiotic germ cells and in Sertoli cells, which provide essential support for spermatogenesis. Dmrt1 null mutant mice have severely dysgenic testes in which Sertoli cells and germ cells both fail to differentiate properly after birth. Here we use conditional gene targeting to identify the functions of Dmrt1 in each cell type. We find that Dmrt1 is required in Sertoli cells for their postnatal differentiation, and for germ line maintenance and for meiotic progression. Dmrt1 is required in germ cells for their radial migration to the periphery of the seminiferous tubule where the spermatogenic niche will form, for mitotic reactivation and for survival beyond the first postnatal week. Thus Dmrt1 activity is required autonomously in the Sertoli and germ cell lineages, and Dmrt1 activity in Sertoli cells is also required non-autonomously to maintain the germ line. These results demonstrate that Dmrt1 plays multiple roles in controlling the remodeling and differentiation of the juvenile testis.

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    ABSTRACT: Spermatogenesis is a continuous and productive process supported by the self-renewal and differentiation of spermatogonial stem cells (SSCs), which arise from undifferentiated precursors known as gonocytes and are strictly controlled in a special "niche" microenvironment in the seminiferous tubules. Sertoli cells, the only somatic cell type in the tubules, directly interact with SSCs to control their proliferation and differentiation through the secretion of specific factors. Spermatocyte meiosis is another key step of spermatogenesis that is regulated by Sertoli cells on the luminal side of the blood-testis barrier (BTB) through paracrine signaling. In this review, we mainly focus on the role of Sertoli cells in the regulation of SSC self-renewal and spermatocyte meiosis, with particular emphasis on paracrine and endocrine-mediated signaling pathways. Sertoli cell growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2), as well as Sertoli cell transcription factors, such as Ets variant 5 (ERM; also known as ETV5), Nociceptin, Neuregulin 1 (NRG1) and androgen receptor (AR), have been identified as the most important upstream factors that regulate SSC self-renewal and spermatocyte meiosis. Other transcription factor and signaling pathways (GDNF-RET-GFRA1 signaling, FGF2-MAP2K1 signaling, CXCL12-CXCR4 signaling, CCL9-CCR1 signaling, FSH-Nociceptin/Oprl-1, RA/FSH-Neuregulin/ ERBB4 and AR/RB-ARID4A/ARID4B) are also addressed.
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    ABSTRACT: Transcription factors related to the insect sex-determination gene doublesex (DMRT proteins) control sex determination and/or sexual differentiation in diverse metazoans and are implicated in transitions between sex-determining mechanisms during vertebrate evolution [1]. In mice, Dmrt1 is required for male gonadal differentiation in somatic cells and germ cells [2-4]. DMRT1 also maintains male gonadal sex: its loss, even in adults, can trigger sexual cell-fate reprogramming in which male Sertoli cells transdifferentiate into their female equivalents-granulosa cells-and testicular tissue reorganizes to a more ovarian morphology [5]. Here we use a conditional Dmrt1 transgene to show that Dmrt1 is not only necessary but also sufficient to specify male cell identity in the mouse gonad. DMRT1 expression in the ovary silenced the female sex-maintenance gene Foxl2 and reprogrammed juvenile and adult granulosa cells into Sertoli-like cells, triggering formation of structures resembling male seminiferous tubules. DMRT1 can silence Foxl2 even in the absence of the testis-determining genes Sox8 and Sox9. mRNA profiling found that DMRT1 activates many testicular genes and downregulates ovarian genes and single-cell RNA sequencing in transdifferentiating cells identified dynamically expressed candidate mediators of this process. Strongly upregulated genes were highly enriched on chromosome X, consistent with sexually antagonistic functions. This study provides an in vivo example of single-gene reprogramming of cell sexual identity. Our findings suggest a reconsideration of mechanisms involved in human disorders of sex development (DSDs) and empirically support evolutionary models in which loss or gain of Dmrt1 function promotes establishment of new vertebrate sex-determination systems. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    ABSTRACT: Dmrt transcription factors control sex determination or sex-specific differentiation across all invertebrate and vertebrate species, where they have been studied so far. Besides important functions in the reproductive system, also non-gonadal roles have been assigned to several dmrt family members. One example is dmrt5 that was shown to guide neurogenesis in the forebrain of some vertebrates including fish. Here we show that in zebrafish, dmrt5 is also expressed adjacent to the pituitary anlage and later in the anterior pars distalis (aPD) where it organizes differentiation of endocrine cells. We find that pituitary induction, cell survival, proliferation and early lineage specification in the pituitary is independent of dmrt5. Instead, dmrt5 is required for terminal differentiation of corticotropes and gonadotropes. Gene knock-down and mutant analysis revealed that dmrt5 promotes corticotrope differentiation via tbx19 expression while it prevents gonadotrope differentiation in the aPD. In dmrt5 morphants and mutants, reduced corticotrope numbers may result in irregular positioning and reduced maintenance of lactotropes. In conclusion, our study establishes a novel function for dmrt5 for cell differentiation in the anterior pituitary. Intriguingly, its effect on gonadotrope numbers defines a first non-gonadal role for a dmrt family member that appears crucial for the activity of the reproductive system.
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