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Constitutive expression of activated NOTCH1 in fetal Sertoli cells dysregulates factors required for proper gonocyte maintenance and survival.

ABSTRACT: Genome-wide analysis of whole embryonic day 14.5 mouse testes constitutively expressing the activated intracellular domain of NOTCH1 in Sertoli cells. The goal of the study was to identify Sertoli cell expressed genes regulated by Notch signaling, which are critical to gonocyte maintenance and survival. The mouse model was generated by intercrossing anti-Müllerian hormone (Amh)-cre transgenic mice and RosaNICD transgenic mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE37073 | GEO | 2013/02/08

SECONDARY ACCESSION(S): PRJNA158091

REPOSITORIES: GEO

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Project description:Fsh-mediated regulation of zebrafish spermatogenesis includes modulating the expression of testicular growth factors. Here, we study if and how two Sertoli cell-derived Fsh-responsive growth factors, anti-Müllerian hormone (Amh; inhibiting steroidogenesis and germ cell differentiation) and insulin-like growth factor 3 (Igf3; stimulating germ cell differentiation), cooperate in regulating spermatogonial development. In dose response and time course experiments with primary testis tissue cultures, Fsh upregulated igf3 transcript levels and down-regulated amh transcript levels; igf3 transcript levels were more rapidly up-regulated and responded to lower Fsh concentrations than were required to decrease amh mRNA levels. Quantification of immunoreactive Amh and Igf3 on testis sections showed that Fsh increased slightly Igf3 staining but decreased clearly Amh staining. Studying the direct interaction of the two growth factors showed that Amh compromised Igf3-stimulated proliferation of type A (both undifferentiated [Aund] and differentiating [Adiff]) spermatogonia. Also the proliferation of those Sertoli cells associated with Aund spermatogonia was reduced by Amh. To gain more insight into how Amh inhibits germ cell development, we examined Amh-induced changes in testicular gene expression by RNA sequencing. The majority (69%) of the differentially expressed genes was down-regulated by Amh, including several stimulators of spermatogenesis, such as igf3 and steroidogenesis-related genes. At the same time, Amh increased the expression of inhibitory signals, such as inha and id3, or facilitated prostaglandin E2 (PGE2) signaling. Evaluating one of the potentially inhibitory signals, we indeed found in tissue culture experiments that PGE2 promoted the accumulation of Aund at the expense of Adiff and B spermatogonia. Our data suggest that an important aspect of Fsh bioactivity in stimulating spermatogenesis is implemented by restricting the different inhibitory effects of Amh and by counterbalancing them with stimulatory signals, such as Igf3

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Constitutive expression of activated NOTCH1 in fetal Sertoli cells dysregulates factors required for proper gonocyte maintenance and survival.

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