bims-bicyki 2022-01-02 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–01–02
ten papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease.
Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations.
Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.
Corrigendum to: "The Rho kinase (ROCK) inhibitor Y-27632 reduces the β 2-adrenoceptor density but enhance cAMP formation in primary equine bronchial epithelial cells" [Eur. J. Pharmacol. 2021 Sep 15; 907:174323].
[Cellular primary cilia and human diseases].
Myosin VI regulates ciliogenesis by promoting the turnover of the centrosomal/satellite protein OFD1.
ATXN10 Is Required for Embryonic Heart Development and Maintenance of Epithelial Cell Phenotypes in the Adult Kidney and Pancreas.
BBS7-SHH Signaling Activity Regulates Primary Cilia for Periodontal Homeostasis.
Developing a reproducible protocol for culturing functional confluent monolayers of differentiated equine oviduct epithelial cells.
N6-methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal cancer.

PLoS Genet. 2021 Dec 28. 17(12): e1009711

c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease.

Abigail O Smith, Julie A Jonassen, Kenley M Preval, Roger J Davis, Gregory J Pazour.

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2. Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.

DOI: https://doi.org/10.1371/journal.pgen.1009711
Kidney Int. 2021 Dec 22. pii: S0085-2538(21)01164-9. [Epub ahead of print]

Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations.

Nastaran Daneshgar, Peir-In Liang, Renny S Lan, McKenna Horstmann, Lindsay Pack, Gourav Bhardwaj, Christie M Penniman, Brian T O'Neill, Dao-Fu Dai.

  Pregnancy is proposed to aggravate cyst progression in autosomal dominant polycystic kidney disease (ADPKD) but Tolvaptan, the only FDA-approved drug for adult ADPKD, is not recommended for pregnant ADPKD patients because of potential fetal harm. Since pregnancy itself may increase the risk for ADPKD progression, we investigated the safety and efficacy of Elamipretide, a mitochondrial-protective tetrapeptide. Elamipretide was found to ameliorate the progression of kidney disease in pregnant Pkd1RC/RC mice, in parallel with attenuation of ERK1/2 phosphorylation and improvement of mitochondrial supercomplex formation. Furthermore, Elamipretide was found to pass through the placenta and breast milk and ameliorate aggressive infantile polycystic kidney disease without any observed teratogenic or harmful effect. Elamipretide has an excellent safety profile and is currently tested in multiple phase II and phase III clinical trials. These pre-clinical studies support a potential clinical trial of Elamipretide for the treatment of ADPKD, particularly for patients that cannot take Tolvaptan.

Keywords:  elamipretide; mitochondria; polycystic kidney disease; pregnancy

DOI:  https://doi.org/10.1016/j.kint.2021.12.006
Hum Mol Genet. 2021 Nov 19. pii: ddab340. [Epub ahead of print]

Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.

Ming-Yang Chang, Tsung-Inn Tsai, Li-Fang Chou, Shen-Hsing Hsu, Huang-Yu Yang, Cheng-Chieh Hung, Ya-Chung Tian, Albert C M Ong, Chih-Wei Yang.

Metabolic reprogramming is a potential treatment strategy for autosomal dominant polycystic kidney disease (ADPKD). Metformin has been shown to inhibit the early stages of cyst formation in animal models. However, metformin can lead to lactic acidosis in diabetic patients with advanced chronic kidney disease, and its efficacy in ADPKD is still not fully understood. Here, we investigated the effect of metformin in an established hypomorphic mouse model of PKD that presents stable and heritable knockdown of Pkd1. The Pkd1 miRNA transgenic mice of both genders were randomized to receive metformin or saline injections. Metformin was administrated through daily intraperitoneal injection from postnatal day 35 for 4 weeks. Unexpectedly, metformin treatment at a concentration of 150 mg/kg increased disease severity, including kidney-to-body weight ratio, cystic index and plasma BUN levels, and was associated with increased renal tubular cell proliferation and plasma lactate levels. Functional enrichment analysis for cDNA microarrays from kidney samples revealed significant enrichment of several pro-proliferative pathways including β-catenin, hypoxia-inducible factor-1α, protein kinase Cα and Notch signaling pathways in the metformin-treated mutant mice. The plasma metformin concentrations were still within the recommended therapeutic range for type 2 diabetic patients. Short-term metformin treatment in a second Pkd1 hypomorphic model (Pkd1RC/RC) was however neutral. These results demonstrate that metformin may exacerbate late-stage cyst growth associated with the activation of lactate-related signaling pathways in Pkd1 deficiency. Our findings indicate that using metformin in the later stage of ADPKD might accelerate disease progression and call for the cautious use of metformin in these patients.

DOI: https://doi.org/10.1093/hmg/ddab340
Eur J Pharmacol. 2021 Dec 22. pii: S0014-2999(21)00880-3. [Epub ahead of print] 174724

Corrigendum to: "The Rho kinase (ROCK) inhibitor Y-27632 reduces the β 2-adrenoceptor density but enhance cAMP formation in primary equine bronchial epithelial cells" [Eur. J. Pharmacol. 2021 Sep 15; 907:174323].

Linda Marie Schellenberg, Ralf Regenthal, Getu Abraham.

DOI: https://doi.org/10.1016/j.ejphar.2021.174724
Sheng Li Xue Bao. 2021 Dec 25. 73(6): 999-1016

[Cellular primary cilia and human diseases].

Jie Liu, Jie Xu, Qian Chen, Chang-Dong Wang.

Cellular primary cilium, located on the surface of virtually all mammalian cells, is a strictly conserved organelle which regulates cell biological process and maintains cell homeostasis by modulating cell proliferation, differentiation, migration, polarity, signal cascades and other life activities. Some diseases caused by mutations in genes encoding structural proteins or accessory proteins of primary cilia are collectively termed as "ciliopathies", which can occur in embryo, infancy and even adulthood. Ciliopathies not only involve a single organ, but also involve multiple organs and multiple systems, showing variable symptoms and overlapping symptoms. This review mainly summarizes the effects of ciliopathy-associated gene mutations on bone, tooth, skin, liver and bile duct, kidney, brain, retina, heart and other organs, uncovers their molecular mechanisms and provides some novel insights into therapy of ciliopathies.
EMBO Rep. 2021 Dec 27. e54160

Myosin VI regulates ciliogenesis by promoting the turnover of the centrosomal/satellite protein OFD1.

Elisa Magistrati, Giorgia Maestrini, Carlos A Niño, Mariana Lince-Faria, Galina Beznoussenko, Alexandre Mironov, Elena Maspero, Mónica Bettencourt-Dias, Simona Polo.

  The actin motor protein myosin VI is a multivalent protein with diverse functions. Here, we identified and characterised a myosin VI ubiquitous interactor, the oral-facial-digital syndrome 1 (OFD1) protein, whose mutations cause malformations of the face, oral cavity, digits and polycystic kidney disease. We found that myosin VI regulates the localisation of OFD1 at the centrioles and, as a consequence, the recruitment of the distal appendage protein Cep164. Myosin VI depletion in non-tumoural cell lines causes an aberrant localisation of OFD1 along the centriolar walls, which is due to a reduction in the OFD1 mobile fraction. Finally, loss of myosin VI triggers a severe defect in ciliogenesis that could be, at least partially, ascribed to an impairment in the autophagic removal of OFD1 from satellites. Altogether, our results highlight an unprecedent layer of regulation of OFD1 and a pivotal role of myosin VI in coordinating the formation of the distal appendages and primary cilium with important implications for the genetic disorders known as ciliopathies.

Keywords:  OFD1; autophagy receptor; centrioles; myosin VI; primary cilium

DOI:  https://doi.org/10.15252/embr.202154160
Front Cell Dev Biol. 2021 ;9 705182

ATXN10 Is Required for Embryonic Heart Development and Maintenance of Epithelial Cell Phenotypes in the Adult Kidney and Pancreas.

Melissa R Bentley-Ford, Reagan S Andersen, Mandy J Croyle, Courtney J Haycraft, Kelsey R Clearman, Jeremy B Foote, Jeremy F Reiter, Bradley K Yoder.

  Atxn10 is a gene known for its role in cytokinesis and is associated with spinocerebellar ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes nephronophthisis (NPHP) and Joubert syndrome (JBTS), which are caused by the disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here, we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue-specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt ATXN10 systemically at postnatal stages, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial-to-mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively, this study identifies ATXN10 as an essential protein for survival.

Keywords:  acinar-to-ductal metaplasia (ADM); ataxin 10 (ATXN10); cilia; epithelial-to-mesenchymal transition (EMT); heart; kidney; pancreas

DOI:  https://doi.org/10.3389/fcell.2021.705182
Front Cell Dev Biol. 2021 ;9 796274

BBS7-SHH Signaling Activity Regulates Primary Cilia for Periodontal Homeostasis.

Pi En Chang, Shujin Li, Hyun-Yi Kim, Dong-Joon Lee, Yoon Jeong Choi, Han-Sung Jung.

  Objectives: Mechanical stimuli are essential for the maintenance of periodontal ligament (PDL) homeostasis. Although there are several studies on atrophic changes in PDL due to occlusal hypofunction, the underlying mechanism is still unknown. Here, we aimed to explore the changes of gene expression in occlusal hypofunctional PDL and elucidate the related role in maintaining the PDL homeostasis. Methods: To investigate the transcriptomic difference between control and hypofunctional PDL tissue from patients, RNA sequencing was performed on 34 human teeth. The atrophic changes in PDL were evaluated by histological analysis. The effect of the Bardet-Biedl syndrome 7 (BBS7) knockdown was evaluated by the RT-qPCR, Western blot, wound healing, and tubule formation assay. Results: We detected that the expression of BBS7 was downregulated in occlusal hypofunctional PDL through RNA sequencing. Dynamic changes, including the number of periodontal ligament cells, alignment of collagen fibers, diameter of blood vessels, appearance of primary cilia, and torturous oxytalan fibers, were observed following occlusal hypofunction. Furthermore, Sonic hedgehog signaling (Shh) activity was closely associated with BBS7 expression in PDL cells. In addition, the cell migration and angiogenesis were also suppressed by BBS7 knockdown in vitro. Conclusion: We suggest that BBS7 plays an essential role in maintaining Shh signaling activity for PDL homeostasis.

Keywords:  BBS7 gene; occlusal hypofunction; periodontal homeostasis; primary cilia; shh signaling pathway

DOI:  https://doi.org/10.3389/fcell.2021.796274
Biol Reprod. 2021 Dec 28. pii: ioab243. [Epub ahead of print]

Developing a reproducible protocol for culturing functional confluent monolayers of differentiated equine oviduct epithelial cells.

Bart Leemans, Elizabeth G Bromfield, Tom A E Stout, Mabel Vos, Hanna Van Der Ham, Ramada Van Beek, Ann Van Soom, Bart M Gadella, Heiko Henning.

  We describe the development of two methods for obtaining confluent monolayers of polarized, differentiated equine oviduct epithelial cells (EOEC) in Transwell inserts and microfluidic chips. EOECs from the ampulla were isolated post-mortem and seeded either (1) directly onto a microporous membrane as differentiated EOECs (direct seeding protocol) or (2) first cultured to a confluent de-differentiated monolayer in conventional wells, then trypsinized and seeded onto a microporous membrane (re-differentiation protocol). Maintenance or induction of EOEC differentiation in these systems was achieved by air-liquid interface introduction. Monolayers cultured via both protocols were characterized by columnar, cytokeratin 19-positive EOECs in Transwell inserts. However, only the re-differentiation protocol could be transferred successfully to the microfluidic chips. Integrity of the monolayers was confirmed by transepithelial resistance measurements, tracer flux and the demonstration of an intimate network of tight junctions. Using the direct protocol, 28% of EOECs showed secondary cilia at the apical surface in a diffuse pattern. In contrast, re-differentiated polarized EOECs rarely showed secondary cilia in either culture system (>90% of the monolayers showed <1% ciliated EOECs). Occasionally (5-10%), re-differentiated monolayers with 11-27% EOECs with secondary cilia in a diffuse pattern were obtained. Additionally, nuclear progesterone receptor expression was found to be inhibited by simulated luteal phase hormone concentrations, and sperm binding to cilia was higher for re-differentiated EOEC monolayers exposed to estrogen-progesterone concentrations mimicking the follicular rather than luteal phase. Overall, a functional equine oviduct model was established with close morphological resemblance to in vivo oviduct epithelium.

Keywords:  Transwell culture; cilia; equine; microfluidic chip; oviduct; primary cell culture

DOI:  https://doi.org/10.1093/biolre/ioab243
Gastroenterology. 2021 Dec 27. pii: S0016-5085(21)04165-2. [Epub ahead of print]

N6-methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal cancer.

Shiyan Wang, Shanshan Gao, Yong Zeng, Lin Zhu, Yulin Mo, Chi Chun Wong, Yi Bao, Peiran Su, Jianning Zhai, Lina Wang, Fraser Soares, Xin Xu, Huarong Chen, Kebria Hezaveh, Xinpei Ci, Aobo He, Tracy McGaha, Catherine O'Brien, Robert Rottapel, Wei Kang, Jianfeng Wu, Gang Zheng, Zongwei Cai, Jun Yu, Housheng Hansen He.

   BACKGROUND & AIMS: N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated.
METHODS: Ythdf1 knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-ARHGEF2 was evaluated using siRNA encapsulated by lipid nanoparticles (LNP).
RESULTS: DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids, and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 mRNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo.
CONCLUSIONS: We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.

Keywords:  ARHGEF2; N6-methyladenosine; YTHDF1; colorectal cancer; nanoparticle

DOI:  https://doi.org/10.1053/j.gastro.2021.12.269