bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021–09–19
sixteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Long-term Benefits of Treatment with Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.
  2. Pulmonary Embolism in Autosomal Dominant Polycystic Kidney Patient Induced by Inferior Vena Cava Mechanical Compression.
  3. Superresolution microscopy reveals photoreceptor-specific subciliary location and function of ciliopathy-associated protein, Cep290.
  4. Urinary Aquaporin 2 as a Potential Indicator Predicting Tolvaptan Response in Patients With ADPKD.
  5. Primary Cilia-Related Pathways Moderate the Development and Therapy Resistance of Glioblastoma.
  6. FBW7 couples structural integrity with functional output of primary cilia.
  7. Primary cilia in hard tissue development and diseases.
  8. Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression.
  9. Preimplantation Genetic Testing for Kidney Disease-Related Genes: A Laboratory's Experience.
  10. 10-Year Evaluation of Adherence and Satisfaction with Information about Tolvaptan in ADPKD: A Single-Center Pilot Study.
  11. RAS induced senescence of skin keratinocytes is mediated through Rho-associated protein kinase (ROCK).
  12. Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes.
  13. Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5.
  14. Exploring the influence of cytosolic and membrane FAK activation on YAP/TAZ nuclear translocation through a 3D computational approach.
  15. RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury.
  16. ARHGAP4-SEPT2-SEPT9 complex enables both up- and down-modulation of integrin-mediated focal adhesions, cell migration, and invasion.
  1. J Nippon Med Sch. 2021 Sep 14.
    Long-term Benefits of Treatment with Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.
    Naoko Shimoda, Mariko Ikeda, Tomohiro Yan, Sayuri Kawasaki, Akio Hirama, Tetsuya Kashiwagi, Yukinao Sakai.
       BACKGROUND: Tolvaptan is the first effective drug treatment for autosomal dominant polycystic kidney disease (ADPKD) patients, but few long-term observations of the effects of tolvaptan have been reported.
    METHODS: In this single center, retrospective cohort study, we investigated nine patients who participated in a phase 3 trial of tolvaptan for ADPKD patients at our hospital between 2008 and 2014. Six of the patients discontinued tolvaptan at the end of the clinical trial and were defined as the discontinuation group, and three continued to take it; these were defined as the continuation group. The observation period was 3 years before and after the end of the tolvaptan trial, and we compared the following data in each group: serum creatinine, estimated glomerular filtration rate (eGFR), total kidney volume, serum sodium concentration, and urine specific gravity.
    RESULTS: eGFR was significantly improved after the end of the trial in the continuation group (P = 0.0446), but there was no significant change in the regression line before and after the end of the trial in the discontinuation group. The increases in mean total kidney volume rates over the 3 years before and after the trial were 0.01 %/year vs. 0.067 %/year in the discontinuation group (P = 0.0247). On the other hand, serum sodium concentration and urine specific gravity showed no change during the observation period.
    CONCLUSION: This study suggested that long-term administration of tolvaptan may improve renal function and inhibit total kidney volume growth.
    Keywords:  autosomal dominant polycystic kidney disease; long-term treatment; renal function; tolvaptan; total kidney volume
    DOI:  https://doi.org/10.1272/jnms.JNMS.2022_89-303
  2. Eur J Case Rep Intern Med. 2021 ;8(8): 002767
    Pulmonary Embolism in Autosomal Dominant Polycystic Kidney Patient Induced by Inferior Vena Cava Mechanical Compression.
    Maamoun Basheer, Elias Saad, Nimer Assy.
       Introduction: Autosomal dominant polycystic kidney disease is a common syndrome. Renal and hepatic cysts can cause discomfort, bleeding, rupture, infection, hypertension and a mass effect with compression of adjacent organs.
    Case presentation: A 48-year-old man with polycystic kidney disease and hypertension presented to the emergency department for bilateral flank pain. An abdominal computed tomography scan with contrast showed a 7 cm heterogeneous process posteriorly and laterally to the right kidney. It appeared to be a renal cyst associated with bleeding and bilateral pulmonary artery filling defects, apparently due to pulmonary embolism. Cavography following inferior vena cava filter insertion did not show any deep vein thrombosis.
    Discussion and conclusion: The pulmonary embolism was probably caused by extrinsic inferior vena cava compression by a liver cyst. Virchow's triad of stasis, vessel damage and hypercoagulability probably resulted in a thrombus which moved on the right side to the pulmonary artery.
    LEARNING POINTS: Autosomal dominant polycystic kidney disease is a common syndrome.Renal and hepatic cysts can compress adjacent organs.The mass effect of a large cyst on the right side compressed the inferior vena cava, resulting in Virchow's triad of stasis, vessel damage and hypercoagulability, which can cause pulmonary embolism.
    Keywords:  Autosomal dominant polycystic kidney disease; inferior vena cava; pulmonary embolism; renal cyst
    DOI:  https://doi.org/10.12890/2021_002767
  3. JCI Insight. 2021 Sep 14. pii: 145256. [Epub ahead of print]
    Superresolution microscopy reveals photoreceptor-specific subciliary location and function of ciliopathy-associated protein, Cep290.
    Valencia L Potter, Abigail R Moye, Michael A Robichaux, Theodore G Wensel.
      Mutations in the cilium-associated protein CEP290 cause retinal degeneration as part of multi-organ ciliopathies or as retina-specific diseases. The precise location and the functional roles of CEP290 within cilia and, specifically, the connecting cilia (CC) of photoreceptors, remain unclear. We used superresolution fluorescence microscopy and electron microscopy (TEM) to localize CEP290 in the CC and in primary cilia of cultured cells with sub-diffraction resolution, and to determine effects of CEP290 deficiency in three mutant models. Radially, CEP290 localizes in close proximity to the microtubule doublets in the region between the doublets and the ciliary membrane. Longitudinally, it is distributed throughout the length of the CC whereas it is confined to the very base of primary cilia in hRPE-1 cells. We found Y-shaped links, ciliary sub-structures between microtubules and membrane, throughout the length of the CC. Severe CEP290 deficiencies in mouse models did not prevent assembly of cilia or cause obvious mislocalization of ciliary components in early stages of degeneration. There were fewer cilia and no normal outer segments in the mutants, but the Y-shaped links were clearly present. These results point to photoreceptor-specific functions of CEP290 essential for CC maturation and stability following the earliest stages of ciliogenesis.
    Keywords:  Cell Biology; Genetic diseases; Mouse models; Ophthalmology; Retinopathy
    DOI:  https://doi.org/10.1172/jci.insight.145256
  4. Kidney Int Rep. 2021 Sep;6(9): 2436-2444
    Urinary Aquaporin 2 as a Potential Indicator Predicting Tolvaptan Response in Patients With ADPKD.
    Shiho Makabe, Shun Manabe, Hiroshi Kataoka, Taro Akihisa, Rie Yoshida, Yusuke Ushio, Masayo Sato, Ken Tsuchiya, Toshio Mochizuki, Kosaku Nitta.
       Introduction: Tolvaptan is used to treat autosomal dominant polycystic kidney disease (ADPKD) because it inhibits binding of the antidiuretic hormone vasopressin to the vasopressin V2 receptor (V2R), which suppresses the insertion of preformed water channel aquaporin 2 (AQP2) molecules in the luminal membrane of the collecting duct cells.
    Methods: This single-center, prospective observational cohort study investigated whether decreased AQP2 elimination in urine affects the renal prognosis of patients who received tolvaptan. We selected 92 patients with ADPKD who were administered tolvaptan in our hospital. We evaluated correlations between changes in urinary AQP2 (U-AQP2) and clinical parameters and the annual change in total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) as renal prognostic factors using univariable and multivariable multiple regression analyses.
    Results: The observation period was 2.4 ± 1.5 years. U-AQP2 per milligram of urinary creatinine (U-AQP2/Cr) decreased from 67.8 ± 50.6 to 20.7 ± 15.1 fmol/mg urinary creatinine after 1 month of tolvaptan treatment. This initial change in U-AQP2/Cr was correlated with high baseline U-AQP2/Cr, low baseline eGFR, and a large initial change in eGFR (baseline to 1 month). The initial change in U-AQP2/Cr (baseline to 1 month) was strongly correlated with the annual change in TKV and eGFR in multivariable analysis.
    Conclusion: Initial decrease in U-AQP2/Cr in the first month of treatment reflects the pharmacologic effect of tolvaptan and could be an indicator of renal prognosis during tolvaptan treatment.
    Keywords:  aquaporin; autosomal dominant polycystic kidney disease; estimated glomerular filtration rate; prognostic factor; tolvaptan; total kidney volume
    DOI:  https://doi.org/10.1016/j.ekir.2021.06.033
  5. Front Oncol. 2021 ;11 718995
    Primary Cilia-Related Pathways Moderate the Development and Therapy Resistance of Glioblastoma.
    Minghao Li, Jiaxun Zhang, Haonan Zhou, Rong Xiang.
      As microtubule-based structures, primary cilia are typically present on the cells during the G0 or G1-S/G2 phase of the cell cycle and are closely related to the development of the central nervous system. The presence or absence of this special organelle may regulate the central nervous system tumorigenesis (e.g., glioblastoma) and several degenerative diseases. Additionally, the development of primary cilia can be regulated by several pathways. Conversely, primary cilia are able to regulate a few signaling transduction pathways. Therefore, development of the central nervous system tumors in conjunction with abnormal cilia can be regulated by up- or downregulation of the pathways related to cilia and ciliogenesis. Here, we review some pathways related to ciliogenesis and tumorigenesis, aiming to provide a potential target for developing new therapies at genetic and molecular levels.
    Keywords:  CCRK; HDAC6; LPAR1; PCM1; glioblastoma; primary cilia; sonic hedgehog
    DOI:  https://doi.org/10.3389/fonc.2021.718995
  6. Commun Biol. 2021 Sep 13. 4(1): 1066
    FBW7 couples structural integrity with functional output of primary cilia.
    Eleni Petsouki, Vasileios Gerakopoulos, Nicholas Szeto, Wenhan Chang, Mary Beth Humphrey, Leonidas Tsiokas.
      Structural defects in primary cilia have robust effects in diverse tissues and systems. However, how disorders of ciliary length lead to functional outcomes are unknown. We examined the functional role of a ciliary length control mechanism of FBW7-mediated destruction of NDE1, in mesenchymal stem cell (MSC) differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on primary cilia formation, MSC differentiation to osteoblasts, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are partially rescued in Fbxw7/Nde1-null cells. We also show that NDE1, despite suppressing ciliogenesis, promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that FBW7 controls a protein-protein interaction network coupling ciliary structure and function, which is essential for stem cell differentiation.
    DOI:  https://doi.org/10.1038/s42003-021-02504-4
  7. Front Med. 2021 Sep 13.
    Primary cilia in hard tissue development and diseases.
    Sijin Li, Han Zhang, Yao Sun.
      Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.
    Keywords:  bone; cilium-related bone disease; hard tissue; mechanical sensing; primary cilia; tooth
    DOI:  https://doi.org/10.1007/s11684-021-0829-6
  8. Sci Rep. 2021 Sep 14. 11(1): 18274
    Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression.
    Chaozhe Yang, Naoe Harafuji, Amber K O'Connor, Robert A Kesterson, Jacob A Watts, Amar J Majmundar, Daniela A Braun, Monkol Lek, Kristen M Laricchia, Hanan M Fathy, Shrikant Mane, Shirlee Shril, Friedhelm Hildebrandt, Lisa M Guay-Woodford.
      Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a deleterious splicing variant in CYS1. These findings suggest that mutations in Cys1/CYS1 cause an ARPKD phenotype in mouse and human, respectively, and that the renal cystic phenotype in the mouse is driven by overexpression of the Myc proto-oncogene.
    DOI:  https://doi.org/10.1038/s41598-021-97046-4
  9. Am J Nephrol. 2021 Sep 02. 1-7
    Preimplantation Genetic Testing for Kidney Disease-Related Genes: A Laboratory's Experience.
    Jessica L Chaperon, Nina M Wemmer, Trudy A McKanna, Dinah M Clark, Maggie A Westemeyer, Philippe Gauthier, Yan Bai, Jessica M Coleman.
       INTRODUCTION: Recent literature highlights the clinical utility of genetic testing for patients with kidney disease. Genetic testing provides significant benefits for reproductive risk counseling, including the option of in vitro fertilization with preimplantation genetic testing for monogenic disease (PGT-M). PGT-M allows for a significant reduction in risk for a pregnancy affected with the familial disease. We aim to summarize our experience with PGT-M for genes with kidney involvement as either a primary or secondary feature of the disease.
    METHODS: All PGT-M tests performed by the reference laboratory between September 2010 and July 2020 were reviewed for clinical indication and cases for which the disease tested included a renal component. Each patient referred for PGT-M had an existing molecular genetic diagnosis themselves or in their family. Frequency of each condition, gene, inheritance pattern, and year over year increase in referral cases was analyzed.
    RESULTS: In the study cohort, the most common disease targeted was autosomal dominant polycystic kidney disease, caused by pathogenic variants in the PKD1 or PKD2 genes, which accounted for 16.5% (64/389) of cases. The 5 most common referral indications accounted for 51.9% (202/389) of the cases. Autosomal recessive inheritance accounted for 52.0% (26/50) of conditions for which PGT-M was performed. The number of PGT-M tests performed for conditions that included either primary or secondary kidney disease increased from 5 cases in 2010 to 47 cases in the 2020 study period.
    DISCUSSION/CONCLUSION: These data suggest that the pursuit of PGT-M by couples at risk for passing on conditions with a kidney component is common and has significantly increased since 2010. With this rising trend of patients undergoing PGT-M and the prerequisite of molecular genetic confirmation in the PGT-M process, this study underscores the importance of the reproductive component to a molecular genetic diagnosis for patients with kidney disease, especially as the accessibility of genetic testing and utilization by nephrologists grows.
    Keywords:  Chronic kidney disease; Monogenic kidney disease; Preimplantation genetic testing
    DOI:  https://doi.org/10.1159/000518253
  10. Patient Prefer Adherence. 2021 ;15 1941-1952
    10-Year Evaluation of Adherence and Satisfaction with Information about Tolvaptan in ADPKD: A Single-Center Pilot Study.
    Holger Schirutschke, Peter Gross, Alexander Paliege, Christian Hugo.
       Purpose: Tolvaptan is the only approved drug for the treatment of autosomal dominant polycystic kidney disease (ADPKD) and causes significant polyuria with secondary polydipsia. Up to now, there is no study that examines tolvaptan adherence and satisfaction with information received about tolvaptan in ADPKD patients 10 years after starting tolvaptan therapy.
    Patients and Methods: This pilot study includes 12 ADPKD patients that were formerly enrolled in the tolvaptan registration trials and have continued to use tolvaptan thereafter. Data were collected once via questionnaires on patients' self-reported adherence (MARS-D: Medication Adherence Report Scale - German version) and satisfaction with the information received about tolvaptan (SIMS-D: Satisfaction with Information about Medicines Scale - German version) at the time of the present study. In addition, serum creatinine levels and clinical data were evaluated.
    Results: The MARS-D demonstrated strong adherence to tolvaptan (range of possible score: 5-25; median: 23.5; range of individual results: 5). The SIMS-D showed a high level of satisfaction with the information received about the action and usage of tolvaptan (SIMS-D AU subscale; range of possible score: 0-9; median: 9, range of individual results: 1), but also revealed dissatisfaction regarding the information received about potential problems of tolvaptan in 42% of the participants (SIMS-D PP subscale; range of possible score: 0-8; median: 8, range of individual results: 6). During treatment with tolvaptan, the eGFR decreased from 78.8 ± 15.9 mL/min/1.73 m2 to 48.3 ± 19.4 mL/min/1.73 m2 (P < 0.0001).
    Conclusion: Although patients reported strong adherence to tolvaptan, there was still dissatisfaction with the information received about potential problems with tolvaptan. Therefore, our data suggest conduction of at least one patient survey on adherence and satisfaction with the information received about tolvaptan during any tolvaptan treatment to improve patient education regarding the use of tolvaptan in slowing down of ADPKD.
    Keywords:  ADPKD; MARS; SIMS; eGFR; tolvaptan
    DOI:  https://doi.org/10.2147/PPA.S325738
  11. Mol Carcinog. 2021 Sep 17.
    RAS induced senescence of skin keratinocytes is mediated through Rho-associated protein kinase (ROCK).
    Alex J Lee, Elise Fraser, Brittany Flowers, Jee Kim, Kenneth Wong, Christophe Cataisson, Huaitian Liu, Howard Yang, Maxwell P Lee, Stuart H Yuspa, Luowei Li.
      Cellular senescence is a well-documented response to oncogene activation in many tissues. Multiple pathways are invoked to achieve senescence indicating its importance to counteract the transforming activities of oncogenic stimulation. We now report that the Rho-associated protein kinase (ROCK) signaling pathway is a critical regulator of oncogene-induced senescence in skin carcinogenesis. Transformation of mouse keratinocytes with oncogenic RAS upregulates ROCK activity and initiates a senescence response characterized by cell enlargement, growth inhibition, upregulation of senescence associated β-galactosidase (SAβgal) expression, and release of multiple pro-inflammatory factors comprising the senescence-associated secretory phenotype (SASP). The addition of the ROCK inhibitor Y-27632 and others prevents these senescence responses and maintains proliferating confluent RAS transformed keratinocyte cultures indefinitely. Mechanistically, oncogenic RAS transformation is associated with upregulation of cell cycle inhibitors p15Ink4b , p16Ink4a , and p19Arf and downregulation of p-AKT, all of which are reversed by Y-27632. RNA-seq analysis of Y-27632 treated RAS-transformed keratinocytes indicated that the inhibitor reduced growth-inhibitory gene expression profiles and maintained expression of proliferative pathways. Y-27632 also reduced the expression of NF-κB effector genes and the expression of IκBζ downstream mediators. The senescence inhibition from Y-27632 was reversible, and upon its removal, senescence reoccurred in vitro with rapid upregulation of cell cycle inhibitors, SASP expression, and cell detachment. Y-27632 treated cultured RAS-keratinocytes formed tumors in the absence of the inhibitor when placed in skin orthografts suggesting that factors in the tumor microenvironment can overcome the drive to senescence imparted by overactive ROCK activity.
    Keywords:  RAS; ROCK; keratinocytes; oncogene; senescence
    DOI:  https://doi.org/10.1002/mc.23351
  12. Clin Exp Nephrol. 2021 Sep 18.
    Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes.
    Shinya Ishiko, Naoya Morisada, Atsushi Kondo, Sadayuki Nagai, Yuya Aoto, Eri Okada, Rini Rossanti, Nana Sakakibara, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Takeshi Ninchoji, Hiroshi Kaito, Riku Hamada, Yuko Shima, Koichi Nakanishi, Masafumi Matsuo, Kazumoto Iijima, Kandai Nozu.
       BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population.
    METHODS: We conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes.
    RESULTS: PKHD1 pathogenic variants were identified in 32 patients (0-46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1-2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808 + 1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities.
    CONCLUSION: Clinical manifestations ranged from cases of neonatal demise to those diagnosed in adulthood. The minigene assay results indicate the importance of functional analysis, and call into question the fundamental belief that at least one non-truncating mutation is necessary for perinatal survival.
    Keywords:  Autosomal recessive polycystic kidney disease; Congenital hypothyroidism; Hepatic fibrosis; Minigene assay; PKHD1
    DOI:  https://doi.org/10.1007/s10157-021-02135-3
  13. Nat Commun. 2021 Sep 16. 12(1): 5482
    Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5.
    Markus Maerker, Maike Getwan, Megan E Dowdle, Jason C McSheene, Vanessa Gonzalez, José L Pelliccia, Danielle S Hamilton, Valeria Yartseva, Charles Vejnar, Melanie Tingler, Katsura Minegishi, Philipp Vick, Antonio J Giraldez, Hiroshi Hamada, Rebecca D Burdine, Michael D Sheets, Martin Blum, Axel Schweickert.
      Rotating cilia at the vertebrate left-right organizer (LRO) generate an asymmetric leftward flow, which is sensed by cells at the left LRO margin. Ciliary activity of the calcium channel Pkd2 is crucial for flow sensing. How this flow signal is further processed and relayed to the laterality-determining Nodal cascade in the left lateral plate mesoderm (LPM) is largely unknown. We previously showed that flow down-regulates mRNA expression of the Nodal inhibitor Dand5 in left sensory cells. De-repression of the co-expressed Nodal, complexed with the TGFß growth factor Gdf3, drives LPM Nodal cascade induction. Here, we show that post-transcriptional repression of dand5 is a central process in symmetry breaking of Xenopus, zebrafish and mouse. The RNA binding protein Bicc1 was identified as a post-transcriptional regulator of dand5 and gdf3 via their 3'-UTRs. Two distinct Bicc1 functions on dand5 mRNA were observed at pre- and post-flow stages, affecting mRNA stability or flow induced translational inhibition, respectively. To repress dand5, Bicc1 co-operates with Dicer1, placing both proteins in the process of flow sensing. Intriguingly, Bicc1 mediated translational repression of a dand5 3'-UTR mRNA reporter was responsive to pkd2, suggesting that a flow induced Pkd2 signal triggers Bicc1 mediated dand5 inhibition during symmetry breakage.
    DOI:  https://doi.org/10.1038/s41467-021-25464-z
  14. Biophys J. 2021 Sep 09. pii: S0006-3495(21)00743-8. [Epub ahead of print]
    Exploring the influence of cytosolic and membrane FAK activation on YAP/TAZ nuclear translocation through a 3D computational approach.
    Kerbaï Saïd Eroumé, Rachel Cavill, Katerina Staňková, Jan de Boer, Aurélie Carlier.
      Membrane binding and unbinding dynamics play a crucial role in the biological activity of several non-integral membrane proteins, which have to be recruited to the membrane in order to perform their functions. By localizing to the membrane, these proteins are able to induce downstream signal amplification in their respective signaling pathways. Here we present a 3D computational approach using reaction-diffusion equations to investigate the relation between membrane localization of Focal Adhesion Kinase (FAK), Ras homolog family member A (RhoA) and signal amplification of the YAP/TAZ signaling pathway. Our results show that the theoretical scenarios, in which FAK is membrane-bound, yield robust and amplified YAP/TAZ nuclear translocation signals. Moreover, we predict that the amount of YAP/TAZ nuclear translocation increases with cell spreading, confirming the experimental findings in the literature. In summary, our in silico predictions show that when the cell membrane interaction area with the underlying substrate increases, for example through cell spreading, this leads to more encounters between membrane-bound signaling partners and downstream signal amplification. Since membrane activation is a motif common to many signaling pathways, this study has important implications for understanding the design principles of signaling networks.
    Keywords:  FAK; Membrane binding/unbinding; YAP/TAZ; cell spreading; computational modeling; signal amplification
    DOI:  https://doi.org/10.1016/j.bpj.2021.09.009
  15. Neuron. 2021 Sep 03. pii: S0896-6273(21)00611-5. [Epub ahead of print]
    RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury.
    Sina Stern, Brett J Hilton, Emily R Burnside, Sebastian Dupraz, Emily E Handley, Jessica M Gonyer, Cord Brakebusch, Frank Bradke.
      An inhibitory extracellular milieu and neuron-intrinsic processes prevent axons from regenerating in the adult central nervous system (CNS). Here we show how the two aspects are interwoven. Genetic loss-of-function experiments determine that the small GTPase RhoA relays extracellular inhibitory signals to the cytoskeleton by adapting mechanisms set in place during neuronal polarization. In response to extracellular inhibitors, neuronal RhoA restricts axon regeneration by activating myosin II to compact actin and, thereby, restrain microtubule protrusion. However, astrocytic RhoA restricts injury-induced astrogliosis through myosin II independent of microtubules by activating Yes-activated protein (YAP) signaling. Cell-type-specific deletion in spinal-cord-injured mice shows that neuronal RhoA activation prevents axon regeneration, whereas astrocytic RhoA is beneficial for regenerating axons. These data demonstrate how extracellular inhibitors regulate axon regeneration, shed light on the capacity of reactive astrocytes to be growth inhibitory after CNS injury, and reveal cell-specific RhoA targeting as a promising therapeutic avenue.
    Keywords:  F-actin density; RhoA; YAP signaling; astrocyte reactivity; axon regeneration; microtubule protrusion; myosin II
    DOI:  https://doi.org/10.1016/j.neuron.2021.08.014
  16. Mol Biol Cell. 2021 Sep 15. mbcE21010010
    ARHGAP4-SEPT2-SEPT9 complex enables both up- and down-modulation of integrin-mediated focal adhesions, cell migration, and invasion.
    Kang Na, Tsubasa S Matsui, Liu Shiyou, Shinji Deguchi.
      The Rho family of GTPases are inactivated in a cell context-dependent manner by Rho-GTPase-activating proteins (Rho-GAPs), but their signaling mechanisms are poorly understood. Here we demonstrate that ARHGAP4, the Rho-GAPs, forms a complex with SEPT2 and SEPT9 via its Rho-GAP domain and SH3 domain to enable both up- and down-modulation of integrin-mediated focal adhesions (FAs). We show that silencing ARHGAP4 as well as overexpressing its two mutually independent upstream regulators SEPT2 and SEPT9 all induce reorganization of FAs to newly express Integrin Beta 1 and also enhance both cell migration and invasion. Interestingly, even if these cell migration/invasion-associated phenotypic changes are induced upon perturbations to the complex, it does not necessarily cause enhanced clustering of FAs. Instead, its extent depends on whether the microenvironment contains ligands suitable for the upregulated Integrin Beta 1. These results provide novel insights to cell migration, invasion, and microenvironment-dependent phenotypic changes regulated by the newly identified complex.
    DOI:  https://doi.org/10.1091/mbc.E21-01-0010
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