Head formation requires Dishevelled degradation that is mediated by March2 in concert with Dapper1

Lee, Hye-Yoon; Cheong, Seong-Moon; Han, Wonhee; Koo, Youngmu; Jo, Saet-Byeol; Cho, Gun-Sik; Yang, Jun; Kim, Sanguk; Han, Jin‐Kwan

doi:10.1242/dev.143107

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…Embryos were injected at one-cell stage into animal pole with mRNAs. Injected and un-injected embryos were dissected at stage 9.5 to perform immunofluorescence as described in Lee et al (2018) 58 . Dissected animal caps were fixed in 4% paraformaldehyde for 2 h and incubated in PBSTB (0.5% Triton-X, 2% BSA in PBS) for 1 h. The animal caps were incubated with primary antibody for overnight at 4 °C and washed with PBS.…”

Section: Identification Of Binding Sites Of Transcription Factors Andmentioning

confidence: 99%

Foxd4l1.1 negatively regulates transcription of neural repressor ventx1.1 during neuroectoderm formation in Xenopus embryos

Kumar

Umair

Kim

et al. 2020

Sci Rep

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Neuroectoderm formation is the first step in development of a proper nervous system for vertebrates. The developmental decision to form a non-neural ectoderm versus a neural one involves the regulation of BMP signaling, first reported many decades ago. However, the precise regulatory mechanism by which this is accomplished has not been fully elucidated, particularly for transcriptional regulation of certain key transcription factors. BMP4 inhibition is a required step in eliciting neuroectoderm from ectoderm and Foxd4l1.1 is one of the earliest neural genes highly expressed in the neuroectoderm and conserved across vertebrates, including humans. In this work, we focused on how Foxd4l1.1 downregulates the neural repressive pathway. Foxd4l1.1 inhibited BMP4/Smad1 signaling and triggered neuroectoderm formation in animal cap explants of Xenopus embryos. Foxd4l1.1 directly bound within the promoter of endogenous neural repressor ventx1.1 and inhibited ventx1.1 transcription. Foxd4l1.1 also physically interacted with Xbra in the nucleus and inhibited Xbra-induced ventx1.1 transcription. In addition, Foxd4l1.1 also reduced nuclear localization of Smad1 to inhibit Smad1-mediated ventx1.1 transcription. Foxd4l1.1 reduced the direct binding of Xbra and Smad1 on ventx1.1 promoter regions to block Xbra/Smad1-induced synergistic activation of ventx1.1 transcription. Collectively, Foxd4l1.1 negatively regulates transcription of a neural repressor ventx1.1 by multiple mechanisms in its exclusively occupied territory of neuroectoderm, and thus leading to primary neurogenesis. In conjunction with the results of our previous findings that ventx1.1 directly represses foxd4l1.1, the reciprocal repression of ventx1.1 and foxd4l1.1 is significant in at least in part specifying the mechanism for the non-neural versus neural ectoderm fate determination in Xenopus embryos.

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Section: Identification Of Binding Sites Of Transcription Factors Andmentioning

confidence: 99%

Foxd4l1.1 negatively regulates transcription of neural repressor ventx1.1 during neuroectoderm formation in Xenopus embryos

Kumar

Umair

Kim

et al. 2020

Sci Rep

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“…The ␤-blocker carvedilol induces MARCH2-dependent ubiquitination of ␤ 2 -adrenergic receptors, leading to its endocytosis and lysosomal trafficking (18). Other known substrates of MARCH2 include cystic fibrosis transmembrane conductance regulator (CFTR) (16,19) and Dishevelled (20). Although MARCH2 functions in vesicular trafficking, it is not known whether trafficking between the ER and Golgi is regulated by the ligase activity of MARCH2.…”

mentioning

confidence: 99%

The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of secretory proteins

Yoo

Cho

Kim

et al. 2019

Journal of Biological Chemistry

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The E3 ubiquitin ligase membrane-associated ring-CH–type finger 2 (MARCH2) is known to be involved in intracellular vesicular trafficking, but its role in the early secretory pathway between the endoplasmic reticulum (ER) and Golgi compartments is largely unknown. Human ER–Golgi intermediate compartment protein 2 (ERGIC2) and ERGIC3 are orthologs of Erv41 and Erv46 in yeast, proteins that form a heteromeric complex, cycle between the ER and Golgi, and function as cargo receptors in both anterograde and retrograde protein trafficking. Here, we report that MARCH2 directs ubiquitination and subsequent degradation of ERGIC3 and that MARCH2 depletion increases endogenous ERGIC3 levels. We provide evidence that the lysine residues at positions 6 and 8 of ERGIC3 are the major sites of MARCH2-mediated ubiquitination. Of note, MARCH2 did not significantly decrease the levels of an ERGIC3 variant with lysine-to-arginine substitutions at residues 6 and 8. We also show that ERGIC3 binds to itself or to ERGIC2, whereas ERGIC2 is unable to interact with itself. Our results indicate that α1-antitrypsin and haptoglobin are likely to be cargo proteins of ERGIC3. We further observed that α1-antitrypsin and haptoglobin specifically bind to ERGIC3 and that ERGIC3 depletion decreases their secretion. Moreover, MARCH2 reduced secretion of α1-antitrypsin and haptoglobin, and coexpression of the ubiquitination-resistant ERGIC3 variant largely restored their secretion, suggesting that MARCH2-mediated ERGIC3 ubiquitination is the major cause of the decrease in trafficking of ERGIC3-binding secretory proteins. Our findings provide detailed insights into the regulation of the early secretory pathway by MARCH2 and into ERGIC3 function.

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“…The study in the Xenopus model shows that another RING-type ubiquitin ligase membrane-associated ring-CH-type finger (MARCH2) is targeting Dishevelled during head development. The MARCH2 interaction with Dishevelled is dependent on the Dishevelled interaction partner Dapper1, and ubiquitinated Dishevelled is degraded in the lysosomal compartment [68].…”

Section: Wnt Signaling Pathway and Its Regulation By Ubiquitin Ligmentioning

confidence: 99%

Ubiquitin Ligases Involved in the Regulation of Wnt, TGF-β, and Notch Signaling Pathways and Their Roles in Mouse Development and Homeostasis

Baloghová

Liďák

Cermak

2019

Genes

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The Wnt, TGF-β, and Notch signaling pathways are essential for the regulation of cellular polarity, differentiation, proliferation, and migration. Differential activation and mutual crosstalk of these pathways during animal development are crucial instructive forces in the initiation of the body axis and the development of organs and tissues. Due to the ability to initiate cell proliferation, these pathways are vulnerable to somatic mutations selectively producing cells, which ultimately slip through cellular and organismal checkpoints and develop into cancer. The architecture of the Wnt, TGF-β, and Notch signaling pathways is simple. The transmembrane receptor, activated by the extracellular stimulus, induces nuclear translocation of the transcription factor, which subsequently changes the expression of target genes. Nevertheless, these pathways are regulated by a myriad of factors involved in various feedback mechanisms or crosstalk. The most prominent group of regulators is the ubiquitin–proteasome system (UPS). To open the door to UPS-based therapeutic manipulations, a thorough understanding of these regulations at a molecular level and rigorous confirmation in vivo are required. In this quest, mouse models are exceptional and, thanks to the progress in genetic engineering, also an accessible tool. Here, we reviewed the current understanding of how the UPS regulates the Wnt, TGF-β, and Notch pathways and we summarized the knowledge gained from related mouse models.

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Head formation requires Dishevelled degradation that is mediated by March2 in concert with Dapper1

Cited by 16 publications

References 38 publications

Foxd4l1.1 negatively regulates transcription of neural repressor ventx1.1 during neuroectoderm formation in Xenopus embryos

Foxd4l1.1 negatively regulates transcription of neural repressor ventx1.1 during neuroectoderm formation in Xenopus embryos

The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of secretory proteins

Ubiquitin Ligases Involved in the Regulation of Wnt, TGF-β, and Notch Signaling Pathways and Their Roles in Mouse Development and Homeostasis

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