The Ephrin Signaling Pathway Regulates Morphology and Adhesion of Mouse Granulosa Cells In Vitro1

Buensuceso, Adrian; Deroo, Bonnie J.

doi:10.1095/biolreprod.112.100123

Cited by 25 publications

(22 citation statements)

References 59 publications

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“…It was recently shown that in Efna5 null mice, LH stimulation of the ovulatory genes eras reduced (Buensuceso et al, 2016). However, EFNA5 is an FSH induced ligand (Buensuceso & Deroo, 2013), which was not regulated by hCG stimulus in our study. Therefore, while our data suggest that EPHB1 receptor is phosphorylated by the preovulatory LH surge, they do not shed light on the potential mechanism.…”

Section: Discussioncontrasting

confidence: 66%

“…One of the largest RTK families, Eph/ephrin, classified into two types, A and B, is involved in cell structure and adhesion, where Eph is identified as the receptor and Efn or ephrin are identified as the ligand (Buensuceso & Deroo, 2013). Among them, ephrin-A5 (Efna5) ligand was shown to be induced by FSH in mouse granulosa cells (Buensuceso & Deroo, 2013). The Efna5 knockout mouse model exhibits subfertility (Buensuceso et al, 2016).…”

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confidence: 99%

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Activated receptor tyrosine kinases in granulosa cells of ovulating follicles in mice

Schuermann

Siddappa

Pansera

et al. 2018

Molecular Reproduction Devel

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Successful ovulation requires the actions of gonadotropins along with those mediated by growth factors binding to their receptor tyrosine kinases (RTKs). There are several growth factors such as epidermal growth factor family ligands and interleukins that play a role during ovulation initiated by the preovulatory surge of luteinizing hormone (LH). The aim of this project was to analyze growth factor signaling pathways induced by LH in mouse granulosa cells. Immature female mice were treated with equine chorionic gonadotropin (eCG) followed 48 hr later by human chorionic gonadotropin (hCG) to induce follicular growth and ovulation. We performed protein array analysis where we identified higher phosphorylation of insulin-like growth factor 1 receptor (IGF1R), the fibroblast growth factor receptor 2 (FGFR2) and ephrin receptor B1 (EPHB1) in granulosa cells at 4 hr post-hCG compared to 0 hr hCG (p < 0.05). We report both a significant increase in transcript abundance (p < 0.05) and the phosphorylation level (p < 0.05) of the IGF1R in granulosa cells at hCG4h. The mRNA abundance of the Fgfr2 and Ephb1 receptors remained unaltered upon hCG treatment. Nonetheless, transcript abundance of the fibroblast growth factor 2 (Fgf2) ligand was elevated at hCG4h (p < 0.01). Based on these results we conclude that the preovulatory LH surge activates signaling pathways of IGF1R through increase in the expression of the Igf1r gene in granulosa cells of ovulating follicles in mice. The LH surge also appears to activate FGFR2 IIIc and EPHB1 signaling, although further investigation is required.

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Section: Discussioncontrasting

confidence: 66%

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confidence: 99%

Activated receptor tyrosine kinases in granulosa cells of ovulating follicles in mice

Schuermann

Siddappa

Pansera

et al. 2018

Molecular Reproduction Devel

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“…For example, forskolin, used in the culture media to maintain RGCs in vitro, up-regulates EphA5 transcription in immortalized rat ovarian granulosa (GFSHR-17) cells (44) and human neuroepithelioma cells (SK-N-MC) (45). Forskolin and the resultant increase in cAMP alters RGC axon outgrowth and regeneration and influences retinotectal map formation (46 -51).…”

Section: Klf16 Inhibition Of Rgc Neurite Outgrowth and Effects On Efnmentioning

confidence: 99%

Novel Roles and Mechanism for Krüppel-like Factor 16 (KLF16) Regulation of Neurite Outgrowth and Ephrin Receptor A5 (EphA5) Expression in Retinal Ganglion Cells

Wang¹,

Galvão

Beach³

et al. 2016

Journal of Biological Chemistry

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Regenerative medicine holds great promise for the treatment of degenerative retinal disorders. Krüppel-like factors (KLFs) are transcription factors that have recently emerged as key tools in regenerative medicine because some of them can function as epigenetic reprogrammers in stem cell biology. Here, we show that KLF16, one of the least understood members of this family, is a POU4F2 independent transcription factor in retinal ganglion cells (RGCs) as early as embryonic day 15. When overexpressed, KLF16 inhibits RGC neurite outgrowth and enhances RGC growth cone collapse in response to exogenous ephrinA5 ligands. Ephrin/EPH signaling regulates RGC connectivity. The EphA5 promoter contains multiple GC-and GT-rich KLF-binding sites, which, as shown by ChIP-assays, bind KLF16 in vivo. In electrophoretic mobility shift assays, KLF16 binds specifically to a single KLF site near the EphA5 transcription start site that is required for KLF16 transactivation. Interestingly, methylation of only six of 98 CpG dinucleotides within the EphA5 promoter blocks its transactivation by KLF16 but enables transactivation by KLF2 and KLF15. These data demonstrate a role for KLF16 in regulation of RGC neurite outgrowth and as a methylation-sensitive transcriptional regulator of EphA5 expression. Together, these data identify differential low level methylation as a novel mechanism for regulating KLF16-mediated EphA5 expression across the retina. Because of the critical role of ephrin/EPH signaling in patterning RGC connectivity, understanding the role of KLFs in regulating neurite outgrowth and Eph receptor expression will be vital for successful restoration of functional vision through optic nerve regenerative therapies. Progressive loss of retinal ganglion cells (RGCs)2 leads to blindness in diseases such as glaucoma, the leading cause of irreversible bilateral blindness worldwide (1). Current treatments can slow progression but cannot restore lost vision. Recent advances in generating retinal cells from embryonic and induced pluripotent stem cells have stimulated interest in the potential for neuronal regeneration to treat blindness (2-4). For successful optic nerve regeneration, newly regenerated RGCs will need to extend axons considerable distances to reach the visual centers of the brain, where they must make the correct patterns of termination on post-synaptic neurons to reestablish retinotopic maps. Thus, it is critical to understand the mechanisms that regulate expression of molecules involved in axonal growth and connectivity.Krüppel-like factors (KLFs) are members of the SP/KLF family of transcription factors that are characterized by three zinc finger DNA binding domains near their C terminus (5). KLFs bind to GT-or GC-rich sequences and can function as either transcriptional activators or repressors, depending on the promoter context (6). At least 15 of the 17 members of the KLF transcription factor family are expressed in RGCs, and overexpression of different KLF transcription factors in RGCs, hippocampal neurons, or cor...

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“…The ephrin receptor protein EPHA5 has been localized in MGCs by immunocytochemistry, regulated by FSH, and thought to participate in cell adhesion processes [66]. The transcript with the greatest differential between MGCs and cumulus cells in LAFs was Comp.…”

Section: Transcripts Expressed At Higher Levels In Mgcs Versus Cumulumentioning

confidence: 99%

Transcriptomic Diversification of Developing Cumulus and Mural Granulosa Cells in Mouse Ovarian Follicles1

Wigglesworth

Lee

Emori

et al. 2015

Biology of Reproduction

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Cumulus cells and mural granulosa cells (MGCs) have functionally distinct roles in antral follicles, and comparison of their transcriptomes at a global and systems level can propel future studies on mechanisms underlying their functional diversity. These cells were isolated from small and large antral follicles before and after stimulation of immature mice with gonadotropins, respectively. Both cell types underwent dramatic transcriptomic changes, and differences between them increased with follicular growth. Although cumulus cells of both stages of follicular development are competent to undergo expansion in vitro, they were otherwise remarkably dissimilar with transcriptomic changes quantitatively equivalent to those of MGCs. Gene ontology analysis revealed that cumulus cells of small follicles were enriched in transcripts generally associated with catalytic components of metabolic processes, while those from large follicles were involved in regulation of metabolism, cell differentiation, and adhesion. Contrast of cumulus cells versus MGCs revealed that cumulus cells were enriched in transcripts associated with metabolism and cell proliferation while MGCs were enriched for transcripts involved in cell signaling and differentiation. In vitro and in vivo models were used to test the hypothesis that higher levels of transcripts in cumulus cells versus MGCs is the result of stimulation by oocyte-derived paracrine factors (ODPFs). Surprisingly ∼48% of transcripts higher in cumulus cells than MGCs were not stimulated by ODPFs. Those stimulated by ODPFs were mainly associated with cell division, mRNA processing, or the catalytic pathways of metabolism, while those not stimulated by ODPFs were associated with regulatory processes such as signaling, transcription, phosphorylation, or the regulation of metabolism.

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The Ephrin Signaling Pathway Regulates Morphology and Adhesion of Mouse Granulosa Cells In Vitro1

Cited by 25 publications

References 59 publications

Activated receptor tyrosine kinases in granulosa cells of ovulating follicles in mice

Activated receptor tyrosine kinases in granulosa cells of ovulating follicles in mice

Novel Roles and Mechanism for Krüppel-like Factor 16 (KLF16) Regulation of Neurite Outgrowth and Ephrin Receptor A5 (EphA5) Expression in Retinal Ganglion Cells

Transcriptomic Diversification of Developing Cumulus and Mural Granulosa Cells in Mouse Ovarian Follicles1

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