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Spermatogonial Type 3 Deiodinase Regulates Thyroid Hormone Target Genes in Developing Testicular Somatic Cells.

ABSTRACT: Premature overexposure to thyroid hormone causes profound effects on testis growth, spermatogenesis, and male fertility. We used genetic mouse models of type 3 deiodinase (DIO3) deficiency to determine the genetic programs affected by premature thyroid hormone action and to define the role of DIO3 in regulating thyroid hormone economy in testicular cells. Gene expression profiling in the neonatal testis of DIO3-deficient mice identified 5699 differentially expressed genes. Upregulated and downregulated genes were, respectively, involved according to DAVID analysis with cell differentiation and proliferation. They included anti-Müllerian hormone and genes involved in the formation of the blood-testis barrier, which are specific to Sertoli cells (SCs). They also included steroidogenic genes, which are specific to Leydig cells. Comparison with published data sets of genes enriched in SCs and spermatogonia, and responsive to retinoic acid (RA), identified a subset of genes that were regulated similarly by RA and thyroid hormone. This subset of genes showed an expression bias, as they were downregulated when enriched in spermatogonia and upregulated when enriched in SCs. Furthermore, using a genetic approach, we found that DIO3 is not expressed in SCs, but spermatogonia-specific inactivation of DIO3 led to impaired testis growth, reduced SC number, decreased cell proliferation and, especially during neonatal development, altered gene expression specific to somatic cells. These findings indicate that spermatogonial DIO3 protects testicular cells from untimely thyroid hormone signaling and demonstrate a mechanism of cross-talk between somatic and germ cells in the neonatal testis that involves the regulation of thyroid hormone availability and action.

SUBMITTER: Martinez ME

PROVIDER: S-EPMC6853691 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Spermatogonial Type 3 Deiodinase Regulates Thyroid Hormone Target Genes in Developing Testicular Somatic Cells.

Martinez M Elena ME Lary Christine W CW Karaczyn Aldona A AA Griswold Michael D MD Hernandez Arturo A

Endocrinology 20191201 12

Premature overexposure to thyroid hormone causes profound effects on testis growth, spermatogenesis, and male fertility. We used genetic mouse models of type 3 deiodinase (DIO3) deficiency to determine the genetic programs affected by premature thyroid hormone action and to define the role of DIO3 in regulating thyroid hormone economy in testicular cells. Gene expression profiling in the neonatal testis of DIO3-deficient mice identified 5699 differentially expressed genes. Upregulated and downre ...[more]

PMID: 31621880

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Project description:Adult male fertility depends on spermatogonial stem cells (SSCs) which undergo either self-renewal or differentiation in response to microenvironmental signals. Activin A acts on Sertoli and Leydig cells to regulate key aspects of testis development and function throughout life, including steroid production. Recognising that activin A levels are elevated in many pathophysiological conditions, this study investigates effects of this growth factor on the niche that determines spermatogonial fate. Although activin A can promote differentiation of isolated spermatogonia in vitro, its impacts on SSC and spermatogonial function in vivo are unknown. To assess this, we examined testes of Inha KO mice, which feature elevated activin A levels and bioactivity, and develop gonadal stromal cell tumours as adults. The GFRA1+ SSC-enriched population was more abundant and proliferative in Inha KO compared to wildtype controls, suggesting that chronic elevation of activin A promotes a niche which supports SSC self-renewal. Intriguingly, clusters of GFRA1+/EOMES+/LIN28A- cells, resembling a primitive SSC subset, were frequently observed in tubules adjacent to tumour regions. Transcriptional analyses of Inha KO tumours, tubules adjacent to tumours, and tubules distant from tumour regions revealed disrupted gene expression in each KO group increased in parallel with tumour proximity. Modest transcriptional changes were documented in Inha KO tubules with complete spermatogenesis. Importantly, tumours displaying upregulation of activin responsive genes were also enriched for factors that promote SSC self-renewal, including Gdnf, Igf1, and Fgf2, indicating the tumours generate a supportive microenvironment for SSCs. Tumour cells featured some characteristics of adult Sertoli cells but lacked consistent SOX9 expression and exhibited an enhanced steroidogenic phenotype, which could arise from maintenance or acquisition of a fetal cell identity or acquisition of another somatic phenotype. Tumour regions were also heavily infiltrated with endothelial, peritubular myoid and immune cells, which may contribute to adjacent SSC support. Our data show for the first time that chronically elevated activin A affects SSC fate in vivo. The discovery that testis stromal tumours in the Inha KO mouse create a microenvironment that supports SSC self-renewal but not differentiation offers a strategy for identifying pathways that improve spermatogonial propagation in vitro.

Dataset Information

Spermatogonial Type 3 Deiodinase Regulates Thyroid Hormone Target Genes in Developing Testicular Somatic Cells.

Publications

Spermatogonial Type 3 Deiodinase Regulates Thyroid Hormone Target Genes in Developing Testicular Somatic Cells.

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