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Adamts9 Is Required for Development of Primary Ovarian Follicles and Maintenance of Female Sex in Zebrafish

ABSTRACT: Previous studies have suggested that adamts9 (a disintegrin and metalloprotease with thrombospondin type-1 motifs, member 9), an extracellular matrix (ECM) metalloprotease, participates in primordial germ cell (PGC) migration and necessary for female fertility. In this study, we found that adamts9 knockout (KO) led to reduced body size, and female to male sex conversion in adult mature zebrafish prior to or after 90 days post fertilization (dpf); however, primary sex determination was not affected in early juveniles of adamts9 KO at 35 dpf. Overfeeding and lowering the rearing density rescued growth defects in female adamts9 KO fish but did not rescue defects in ovarian development in adamts9 KO. Delayed PGC proliferation, significantly reduced number and size of Stage IB follicles (equivalent to primary follicle) in early juveniles of adamts9 KO, and arrested development at Stage IB follicles in mid- or late-juveniles of adamts9 KO are likely causes of female infertility and sex conversion. Via RNAseq, we found significant enrichment of differentially expressed genes involved in ECM organization during sexual maturation in ovaries of wildtype fish; and significant dysregulation of these genes in adamts9 KO ovaries. RNAseq analysis also showed enrichment of inflammatory transcriptomic signatures in adult ovaries of these adamts9 KO. Taken together, our results indicate that adamts9 is critical for development of primary ovarian follicles and maintenance of female sex in zebrafish, and loss of adamts9 in zebrafish leads to ovarian follicle arrest, female infertility, and sex conversion in late juveniles and mature adults.

ORGANISM(S): Danio rerio

PROVIDER: GSE264143 | GEO | 2024/04/16

REPOSITORIES: GEO

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Project description:We identify a role for two evolutionarily related, secreted metalloproteases of the ADAMTS family (A disintegrin-like and metalloprotease domain with thrombospondin type-1 motif), ADAMTS20 and ADAMTS9, in palatogenesis. Adamts20 mutations cause the mouse white spotting mutant belted (bt), whereas Adamts9 is essential for survival beyond 7.5 days of gestation (E7.5). Functional overlap of Adamts9 with Adamts20 was established in bt/bt:Adamts9+/- mice, which have increased white spotting relative to bt mice, as previously reported, and a fully penetrant cleft palate. Palatal closure was delayed, although eventually completed, in both bt/+;Adamts9+/- and bt/bt mice, demonstrating a cooperative role of these related genes. Adamts9 and Adamts20 are both expressed in palatal mesenchyme, with Adamts9 expressed exclusively in microvascular endothelial cells. Palatal shelves from bt/bt:Adamts9+/- mice fused in culture, suggesting an intact TGF signaling pathway in palatal epithelium, and indicating a temporally specific delay in palatal shelf elevation and growth toward the midline. Palatal shelf mesenchymal cells showed a statistically significant decrease of cell proliferation at E13.5 and E14.5, as well as decreased processing of versican, an ADAMTS substrate, at these stages. Vcan haploinsufficiency led to a greater penetrance of cleft palate in bt mice, and impaired proliferation was also seen in palatal mesenchymal cells of these mice, suggesting a role for ADAMTS-mediated versican proteolysis in palatal closure. In a parallel with recent work identifying a role for a bioactive ADAMTS-generated versican fragment in regulating apoptosis during interdigital web regression, we propose that versican proteolysis may influence palatal mesenchymal cell proliferation. Palatal shelves were dissected from four E13.75 Adamts9+/-:bt/bt embyos (correspond to the 4 samples: Palate_Adamts9+/-:bt/bt_Rep1, Palate_Adamts9+/-:bt/bt_Rep2, Palate_Adamts9+/-:bt/bt_Rep3 and Palate_Adamts9+/-:bt/bt_Rep4) and age-matched 3 wild-type C57Bl/6 embryos (correspond to the 3 samples: Palate_WT_Rep1, Palate_WT_Rep2, and Palate_WT_Rep3) that were used as the controls

Project description:Purpose: The gene molecular network involved in teleost fish sex determination and differentiation is highly variable among species and even in some cases among populations of the same species. The objectives of the present study were to identify the period of gonadal sex differentiation in tambaqui juveniles, as well as the genes and pathways potentially involved in this process. Methods: Histological analysis of juveniles was carried out to establish a timeline of the gonadal differentiation in tambaqui. Based on that knowledge, ten juveniles were selected before the first evidence of histological sex differentiation and total RNA was extracted from their trunks and used for RNA-Sequencing and a subsequent de novo transcriptome assembly. Principal Component Analysis (PCA) of the whole transcriptome data was used to cluster samples into two distinct groups: putative males and putative females. Differential gene expression, functional annotation and gene enrichment were used to identify genes and pathways related to sex differentiation in tambaqui to which was applied the Mann-Whitney non-parametric t test (p <0.05) confirming the statistical significance of the expression dimorphism between the groups. Results: The first sign of histological sex differentiation in tambaqui was the formation of the ovarian cavity detected in individuals measuring about 40 mm in total length. Before the differentiation period, components of the Wnt / β-catenin pathway, fox and fst genes (p <0.05) suggest female sex development in the putative females, whereas antagonistic pathways (gsk3b, wt1 and fgfr2), sox9 and genes for androgen synthesis (p <0.05) are indicative of a male-like differentiation. Conclusions: Tambaqui juveniles prior to the morphological ovarian differentiation present the Wnt / β-catenin pathway exerting putative role on the sex differentiation target, either upregulated in female-like individuals, or antagonized in male-like individuals. Thus, the present work provides a molecular basis for future studies on the application of tambaqui monosex cultivation.

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Adamts9 Is Required for Development of Primary Ovarian Follicles and Maintenance of Female Sex in Zebrafish

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