JNK signaling regulates E-cadherin junctions in germline cysts and determines primordial follicle formation in mice

Niu, Wanbao; Wang, Ye; Wang, Zhengpin; Xin, Qiliang; Wang, Yijing; Feng, Lizhao; Zhao, Lihua; Wen, Jing; Zhang, Hua; Wang, Chao; Xia, Guoliang

doi:10.1242/dev.132175

Cited by 30 publications

(33 citation statements)

References 46 publications

(23 reference statements)

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“…Recent studies have implied that inhibition of JNK enhances Ecadherin redistribution to plasma membrane and promotes adherens junctions formation (16,17). Niu et al (18) show that JNK regulates E-cadherin degradation through the E3 ubiquitin ligase MDM2. In addition to evidence that JNK regulates E-cadherin redistribution and stability, our data reveal JNK suppression of E-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

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The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E‐cadherin‐mediated adherens junctions

Wang

Zhao

et al. 2017

FASEB j.

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The tumor necrosis factor receptor-associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF-α-mediated signaling pathways. Modulation of TRAF2 activity by ubiquitination is well studied; however, the deubiquitinating enzyme (DUB), which regulates TRAF2 stability, has not been identified. Here we reveal USP48 as the first identified DUB to deubiquitinate and stabilize TRAF2 in epithelial cells. Down-regulation of USP48 increases K48-linked polyubiquitination of TRAF2 and reduces TRAF2 protein levels. Interestingly, USP48 only targets the TRAF2 related to JNK pathway, not the TRAF2 related to NF-κB and p38 pathways. USP48 is serine phosphorylated in response to TNF-α. The phosphorylation is catalyzed by glycogen synthase kinase 3β (GSK3β), ultimately resulting in increases in USP48 DUB activity. Furthermore, we reveal a new biologic function of TRAF2 that contributes to epithelial barrier dysfunction, which is attenuated by knockdown of USP48. Inhibition of TRAF2/JNK pathway increases E (epithelial)-cadherin expression and enhances epithelial barrier integrity, while knockdown of USP48 attenuates TNF-α/JNK pathway and increases E-cadherin expression and cell-cell junction in epithelial cells. These data, taken together, indicate that USP48 stabilizes TRAF2, which is promoted by GSK3β-mediated phosphorylation. Further, down-regulation of USP48 increases E-cadherin expression and epithelial barrier integrity through reducing TRAF2 stability.-Li, S., Wang, D., Zhao, J., Weathington, N. M., Shang, D., Zhao, Y. The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions.

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Section: Discussionmentioning

confidence: 99%

“…While JNK has been shown to play an important role in regulating E-cadherin junctions (16)(17)(18), the effect of TRAF2 on E-cadherin expression has not been studied.…”

mentioning

confidence: 99%

The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E‐cadherin‐mediated adherens junctions

Wang

Zhao

et al. 2017

FASEB j.

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“…To future confirm nZnO toxicity on pregnant mice, the germ cell number at 17.5 dpc (germ cells arrived in diplotene of MPI), 3 dpp (ovarian reservior establishment), 21 dpp (puberty), and 4 - 6 weeks (adult) [ 34 , 35 ] was compared. It was found that nZnO exposure increased the accumulation of DSBs in 17.5 dpc fetal oocytes.…”

Section: Discussionmentioning

confidence: 99%

Exposure to Zinc oxide nanoparticles during pregnancy induces oocyte DNA damage and affects ovarian reserve of mouse offspring

Zhai

Wang

et al. 2018

Aging

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Zinc oxide nanoparticles (nZnO) have been shown to have higher toxic effects likely due to their ion-shedding ability and low solubility under neutral conditions. In order to investigate whether exposure to nZnO during embryonic development affects ovary development, 12.5 day post coitum (dpc) fetal mouse ovaries were cultured in the presence of nZnO for 6 days. We found that the nanoparticles (NPs) accumulated within the oocyte cytoplasm in a dose dependent manner, caused DNA damage and apoptosis, and result in a significant decrease in oocyte numbers. No such effects were observed when the ovaries were incubated in the presence of ZnSO4 or bulk ZnO as controls. In addition, we injected intravenously 16 mg/kg body weight nZnO in 12.5 dpc pregnant mice on two consecutive days and analyzed the ovaries of fetuses or offspring at three critical periods of oogenesis: 17.5 dpc, 3 days post-partum (dpp) and 21 dpp. Evidence of increased DNA damage in pachytene oocytes in fetal ovaries and impaired primordial follicle assembly and folliculogenesis dynamics in the ovaries of the offspring were found. Our results indicate that certain types of NPs affect pre- and post-natal oogenesis in vitro and in vivo.

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“…This Ecadherin decrease is an effect of JNK signaling. The in vitro inhibition of this signaling pathway enhanced the expression of E-cadherin and disrupted cyst breakdown [46]. On the other hand, the in vitro inhibition of E-cadherin accelerated cyst breakdown and primordial follicle formation.…”

Section: Cadherins In Gonad Developmentmentioning

confidence: 95%

“…In the developing ovaries, during the cyst breakdown, specific changes in E-cadherin expression occur. In mice, E-cadherin is initially intensively located at oocyte-oocyte contacts until E17.5, and after that time, the localization of E-cadherin becomes weaker and diffused [46]. The expression of E-cadherin again increases by P4.…”

Section: Cadherins In Gonad Developmentmentioning

confidence: 99%

The Central Role of Cadherins in Gonad Development, Reproduction and Fertility

Piprek

Kloc

Mizia

et al. 2020

Preprint

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Cadherins are a group of membrane proteins responsible for cell adhesion. They are crucial for cell sorting and recognition during the morphogenesis, but also play many other roles such as assuring tissue integrity and resistance to stretching, mechanotransduction, cell signaling, regulation of cell proliferation, apoptosis, survival, carcinogenesis, etc. Within the cadherin superfamily, the E- and N-cadherin have been especially well studied. They are involved in many aspects of sexual development and reproduction, such as germline development and gametogenesis, gonad development and functioning, and fertilization. E-cadherin is expressed in the primordial germ cells, (PGCs) and also participates in PGC migration to the developing gonads where they become enclosed by the N-cadherin-expressing somatic cells. The differential expression of cadherins is also responsible for the establishment of the testis or ovary structure. In the adult testes, the N-cadherin is responsible for the integrity of the seminiferous epithelium, regulation of sperm production, and the establishment of the blood-testis barrier. Sex hormones regulate the expression and turnover of N-cadherin influencing the course of spermatogenesis. In the adult ovaries, E- and N-cadherin assure the integrity of ovarian follicles and the formation of corpora lutea. Cadherins are expressed in the mature gametes, and facilitate the capacitation of sperm in the female reproductive tract, and gamete contact during fertilization. The germ cells and accompanying somatic cells express a series of different cadherins, however, their role in gonads and reproduction is still unknown. In this review, we show what is known and unknown about the role of cadherins in the germline and gonad development, and suggest the topics for future research.

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JNK signaling regulates E-cadherin junctions in germline cysts and determines primordial follicle formation in mice

Cited by 30 publications

References 46 publications

The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E‐cadherin‐mediated adherens junctions

The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E‐cadherin‐mediated adherens junctions

Exposure to Zinc oxide nanoparticles during pregnancy induces oocyte DNA damage and affects ovarian reserve of mouse offspring

The Central Role of Cadherins in Gonad Development, Reproduction and Fertility

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