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Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation.

ABSTRACT: Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-? family, TGF-beta 1 (TGF-?1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-?1 increases the excitatory synapse formation in cortical neurons. Here, we investigated the role of TGF-?1 in glutamatergic cerebellar neurons. We showed that the expression profile of TGF-?1 and its receptor, T?RII, in the cerebellum is consistent with a role in synapse formation in vitro and in vivo. It is low in the early postnatal days (P1-P9), increases after postnatal day 12 (P12), and remains high until adulthood (P30). We also found that granule neurons express the TGF-? receptor mRNA and protein, suggesting that they may be responsive to the synaptogenic effect of TGF-?1. Treatment of granular cell cultures with TGF-?1 increased the number of glutamatergic excitatory synapses by 100%, as shown by immunocytochemistry assays for presynaptic (synaptophysin) and post-synaptic (PSD-95) proteins. This effect was dependent on T?RI activation because addition of a pharmacological inhibitor of TGF-?, SB-431542, impaired the formation of synapses between granular neurons. Together, these findings suggest that TGF-?1 has a specific key function in the cerebellum through regulation of excitatory synapse formation between granule neurons.

SUBMITTER: Araujo AP

PROVIDER: S-EPMC4846658 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation.

Araujo Ana P B AP Diniz Luan P LP Eller Cristiane M CM de Matos Beatriz G BG Martinez Rodrigo R Gomes Flávia C A FC

Frontiers in cellular neuroscience 20160427

Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-β family, TGF-beta 1 (TGF-β1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-β1 increases ...[more]

PMID: 27199658

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Project description:BACKGROUND: Recently, several members of the transforming growth factor-beta (TGF-beta) superfamily have been shown to be essential for regulating the growth and differentiation of ovarian follicles and thus fertility. METHODS: Ovaries of neonatal and adult sheep were examined for expression of the TGF-betas 1-3 and their receptors (RI and RII) by in situ hybridization using ovine cDNAs. The effects of TGF-beta 1 and 2 on proliferation and differentiation of ovine granulosa cells in vitro were also studied. RESULTS: The expression patterns of TGF-beta 1 and 2 were similar in that both mRNAs were first observed in thecal cells of type 3 (small pre-antral) follicles. Expression of both mRNAs continued to be observed in the theca of larger follicles and was also present in cells within the stroma and associated with the vascular system of the ovary. There was no evidence for expression in granulosa cells or oocytes. Expression of TGF-beta 3 mRNA was limited to cells associated with the vascular system within the ovary. TGFbetaRI mRNA was observed in oocytes from the type 1 (primordial) to type 5 (antral) stages of follicular growth and granulosa and thecal cells expressed this mRNA at the type 3 (small pre-antral) and subsequent stages of development. The TGFbetaRI signal was also observed in the ovarian stroma and vascular cells. In ovarian follicles, mRNA encoding TGFbetaRII was restricted to thecal cells of type 3 (small pre-antral) and larger follicles. In addition, expression was also observed in some cells of the surface epithelium and in some stromal cells. In granulosa cells cultured for 6 days, both TGF-beta 1 and 2 decreased, in a dose dependent manner, both the amount of DNA and concentration of progesterone. CONCLUSION: In summary, mRNA encoding both TGF-beta 1 and 2 were synthesized by ovarian theca, stroma and cells of the vascular system whereas TGF-beta 3 mRNA was synthesized by vascular cells. Luteinizing granulosa cells also responded to both TGF-beta 1 and beta 2 in vitro. These findings in sheep are consistent with TGF-beta potentially being an important autocrine regulator of thecal cell function and possibly a paracrine regulator of ovarian cell function at various development stages.

Project description:Transforming growth factor β (TGFβ) signaling regulates multifaceted reproductive processes via its transmembrane receptor complex-associated machinery. It has been shown that the type 1 receptor of TGFβ (TGFBR1) is indispensable for female reproductive tract development, pregnancy success, and fertility. However, the role of TGFβ signaling in decidual development and function remains poorly defined. Our objective is to determine the impact of uterine-specific deletion of Tgfbr1 on the differentiation of endometrial stromal cells in pregnant mice, with a focus on the cellular and molecular properties of the decidua. An approach combining histological and immunohistochemical analyses, quantitative PCR, western blot, and RNA-sequencing was utilized. Our results show that decidual development is altered in TGFBR1 conditionally depleted uteri, substantiated by downregulation of genes associated with inflammatory response and uterine natural killer cell abundance, reduced presence of non-decidualized fibroblasts in the antimesometrial region, and impaired decidual cell differentiation. Notably, conditional ablation of TGFBR1 results in the formation of decidua containing more abundant alpha smooth muscle actin (ACTA2)-positive cells at the peripheral region of the antimesometrial side versus controls. This finding is corroborated by upregulation of a subset of smooth muscle marker genes in Tgfbr1 conditionally-deleted decidua. The abnormal cell differentiation is accompanied with increased cell proliferation and enhanced decidual ERK1/2 signaling upon decidual regression. In summary, this study has identified an important role of TGFBR1 in decidual cell differentiation by revealing that conditional ablation of TGFBR1 in the uterus profoundly impacts the cellular and molecular properties of the decidua. Our results suggest that TGFBR1 is required for the development of an integral decidua, a transient but crucial structure that supports embryo development.

Dataset Information

Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation.

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Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation.

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