Disruption of Robo2-Baiap2 integrated signaling drives cystic disease

Li, Qinggang; Cui, Shaoyuan; Ma, Qian; Liu, Ying; Yu, Hongyu; Geng, Guoxia; Agborbesong, Ewud; Ren, Cheng; Wei, Kai; Zhang, Yingjie; Yang, Jurong; Bai, Xueyuan; Cai, Guangyan; Xie, Yuansheng; Li, Yong; Chen, Xiangmei

doi:10.1172/jci.insight.127602

Cited by 5 publications

(14 citation statements)

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“…Using temporally inducible global Slit2 deletion during midgestational embryonic development, we observed cystic kidney formation similar to that previously described in global Robo2 mutants, suggesting that Slit2 interacts with Robo2 to regulate tubular polarization and ciliogenesis via Baiap2 and p53. 21 As a novel finding, we also observed glomerular angiogenesis defects in the embryonic Slit2 iKO kidneys, supporting proangiogenic effects of Slit2 signaling in glomerular angiogenesis. To better evaluate angiogenesis without the extensive and confounding tubular dilations, we extended the analysis of Slit2-Robo function to the postnatal kidney using a temporal window in the first postnatal week when nephrogenesis in the cortical region of the kidney is still ongoing, whereas it has already been completed in the medullary region.…”

Section: Discussionsupporting

confidence: 73%

“…Further studies showed that Robo2 signaling defects in mice also lead to cystic kidney disease and that Robo2 signaling regulates ciliogenesis, polarization, and differentiation of tubular epithelium via P53 and ciliary proteins. 21 Slit2-Robo2 signaling also affects glomerular podocyte foot processes by interacting with nephrin. 22 Whether Slit-Robo signaling also affects the renal vasculature is still unknown.…”

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confidence: 99%

“…17 –19 Global knockout mouse models showed that Slit2-Robo2 signaling inhibition led to the formation of multiple ureters and perinatal lethality, 20 demonstrating that Slit2-Robo2 signaling functions to restrict the budding of the ureteric epithelium to a single site. Further studies showed that Robo2 signaling defects in mice also lead to cystic kidney disease and that Robo2 signaling regulates ciliogenesis, polarization, and differentiation of tubular epithelium via P53 and ciliary proteins 21 . Slit2-Robo2 signaling also affects glomerular podocyte foot processes by interacting with nephrin 22 .…”

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confidence: 99%

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Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development

Geraldo

Dubrac

et al. 2021

JASN

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BackgroundKidney function requires continuous blood filtration by glomerular capillaries. Disruption of glomerular vascular development or maintenance contributes to the pathogenesis of kidney diseases, but the signaling events regulating renal endothelium development remain incompletely understood. Here, we discovered a novel role of Slit2-Robo signaling in glomerular vascularization. Slit2 is a secreted polypeptide that binds to transmembrane Robo receptors and regulates axon guidance as well as ureteric bud branching and angiogenesis.MethodsWe performed Slit2-alkaline phosphatase binding to kidney cryosections from mice with or without tamoxifen-inducible Slit2 or Robo1 and -2 deletions, and we characterized the phenotypes using immunohistochemistry, electron microscopy, and functional intravenous dye perfusion analysis.ResultsOnly the glomerular endothelium, but no other renal endothelial compartment, responded to Slit2 in the developing kidney vasculature. Induced Slit2 gene deletion or Slit2 ligand trap at birth affected nephrogenesis and inhibited vascularization of developing glomeruli by reducing endothelial proliferation and migration, leading to defective cortical glomerular perfusion and abnormal podocyte differentiation. Global and endothelial-specific Robo deletion showed that both endothelial and epithelial Robo receptors contributed to glomerular vascularization.ConclusionsOur study provides new insights into the signaling pathways involved in glomerular vascular development and identifies Slit2 as a potential tool to enhance glomerular angiogenesis.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

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confidence: 99%

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Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development

Geraldo

Dubrac

et al. 2021

JASN

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“…At one of the best-known MDM2 phosphorylation sites, S166, several new pathways and stimuli have been described, including elevated glucose and modulation of intracellular glycosylation (Barzalobre- Gerónimo et al 2015;de Queiroz et al 2016), the proinflammatory cytokine MIF (Costa et al 2016), nicotine (Chen and Wang 2019), and CD44 through activation of EGFR (Dhar et al 2018). The Robo2-Baiap cascade, involved in axon guidance and neuron migration, is required to maintain MDM2-S166 phosphorylation in kidney cells (Li et al 2019). DNA damage induces phosphorylation at S429 by ATM, thereby enhancing the E3 ligase activity of the MDM2-MDM2 homodimer, but interestingly not the MDM2-MDMX heterodimer (Magnussen et al 2020).…”

Section: Regulation At the Protein Level: Small Changes Can Make A Bi...mentioning

confidence: 99%

The roles and regulation of MDM2 and MDMX: it is not just about p53

et al. 2021

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Most well studied as proteins that restrain the p53 tumor suppressor protein, MDM2 and MDMX have rich lives outside of their relationship to p53. There is much to learn about how these two proteins are regulated and how they can function in cells that lack p53. Regulation of MDM2 and MDMX, which takes place at the level of transcription, post-transcription, and protein modification, can be very intricate and is context-dependent. Equally complex are the myriad roles that these two proteins play in cells that lack wild-type p53; while many of these independent outcomes are consistent with oncogenic transformation, in some settings their functions could also be tumor suppressive. Since numerous small molecules that affect MDM2 and MDMX have been developed for therapeutic outcomes, most if not all designed to prevent their restraint of p53, it will be essential to understand how these diverse molecules might affect the p53-independent activities of MDM2 and MDMX.

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“…Western Blotting. Western blotting was performed as previously described [6]. The isolated mouse kidney was washed with ice-cold PBS, pH 7.4, and lysed with ice-cold RIPA lysis buffer for 1 hour at 4 °C.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

Ganab Haploinsufficiency Does Not Cause Polycystic Kidney Disease or Polycystic Liver Disease in Mice

Geng

Xiao

Zhang

et al. 2020

BioMed Research International

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Background. Heterozygous GANAB mutations that can cause autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD) have been described previously, but their roles in ADPKD and PLD are largely unknown. With the increase in polycystic kidney disease caused by GANAB gene mutations in recent years, a suitable animal model is still needed to further explore the pathogenic role of this gene. Methods. To construct a mouse model of Ganab gene deletion, we analyzed the Ganab gene structure and designed two CRISPR-/Cas9-based targeting strategies. The Cas9/sgRNA we constructed was microinjected into fertilized mouse eggs to obtain chimeric F0 mice. Mice with stable genotypes were selected from offspring born after mating F0 mice with wild-type mice. Results. We found that homozygous mutation of the Ganab gene in C57BL/6 mice resulted in early embryonic lethality, and there were no cysts in the kidneys or livers of Ganab+/- mice. Additionally, Ganab protein expression was reduced by at least 50%, while the expression of ADPKD proteins (PC1 and PC2) and acetylated tubulin was not affected in the Ganab+/- kidney. However, the Ganab+/- mice did not show any abnormal clinical phenotypes after birth and failed to reveal renal tubule dilatation or any abnormalities of the glomeruli in the Ganab+/- kidney. Conclusions. Homozygous Ganab mutations are lethal in the fetal stage, and Ganab haploinsufficiency does not cause kidney or liver cysts in mice, suggesting that it may not be the causative gene in polycystic kidney disease.

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Disruption of Robo2-Baiap2 integrated signaling drives cystic disease

Cited by 5 publications

References 64 publications

Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development

Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development

The roles and regulation of MDM2 and MDMX: it is not just about p53

Ganab Haploinsufficiency Does Not Cause Polycystic Kidney Disease or Polycystic Liver Disease in Mice

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