bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021‒06‒20
fourteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Association of autosomal dominant polycystic kidney disease, asymptomatic multiple giant coronary arteries aneurysms and abdominal aortic aneurysm: a case report.
  2. A case of autosomal dominant polycystic kidney disease with amelioration of refractory cyst infections following prolonged hemodialysis time.
  3. Corneal endothelial cell density and microvascular changes of retina and optic disc in autosomal dominant polycystic kidney disease.
  4. A Multitubular Kidney-on-Chip to Decipher Pathophysiological Mechanisms in Renal Cystic Diseases.
  5. Renal and Skeletal Anomalies in a Cohort of Individuals With Clinically Presumed Hereditary Nephropathy Analyzed by Molecular Genetic Testing.
  6. Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus.
  7. Primary cilium and its role in tumorigenesis.
  8. Rho GTPases in kidney physiology and diseases.
  9. PEA prevented early BBB disruption after cerebral ischaemic/reperfusion (I/R) injury through regulation of ROCK/MLC signaling.
  10. The structural basis of intraflagellar transport at a glance.
  11. Mechanism of Yifei Decoction Combined with MitoQ on Inhibition of TGFβ1/NOX4 and PDGF/ROCK Signal Pathway in Idiopathic Pulmonary Fibrosis.
  12. Multi-dimensional and spatiotemporal correlative imaging at the plasma membrane of live cells to determine the continuum nano-to-micro scale lipid adaptation and collective motion.
  13. Fine-tuning multiciliated cell differentiation at the post-transcriptional level: contribution of miR-34/449 family members.
  14. Combinatorial patterns of graded RhoA activation and uniform F-actin depletion promote tissue curvature.
  1. Oxf Med Case Reports. 2020 Dec;2020(12): omaa122
    Association of autosomal dominant polycystic kidney disease, asymptomatic multiple giant coronary arteries aneurysms and abdominal aortic aneurysm: a case report.
    Abdullah Rida Hindawy, Baraa Daboul, Ibrahem Hanafi, Sami Albitar.
      Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disease characterized by the formation of multiple cysts in several organs. The formation of aneurysms accompanying this disease is being increasingly reported in the literature, and mutations in PKD-1 and PKD-2 are suspected in this etiology. Although the association between ADPKD and multiple coronary arteries aneurysms (CAA) was reported several times, we are presenting a case with the combination of ADPKD, multiple giant CAAs, abdominal aortic aneurysms and a suspected intracranial aneurysm, which has never been reported. The asymptomatic presentation of these multiple aneurysms might support the recommendations for further diagnostic investigations in these patients.
    Keywords:  abdominal aortic aneurysm (AAA); autosomal dominant polycystic kidney disease (ADPKD); case report; coronary artery aneurysm (CAA); giant coronary aneurysm; multiple aneurisms
    DOI:  https://doi.org/10.1093/omcr/omaa122
  2. CEN Case Rep. 2021 Jun 17.
    A case of autosomal dominant polycystic kidney disease with amelioration of refractory cyst infections following prolonged hemodialysis time.
    Norio Ieiri, Osamu Hotta.
      Renal cyst infection is a frequent and serious problem in patients with autosomal dominant polycystic kidney disease (ADPKD). Cyst infection is often a refractory complication of treatment that leads to sepsis and death in patients with ADPKD. It was previously reported that a higher dose of dialysis demonstrated clearly better survival than shorten-time dialysis. The relationship between the frequency of cyst infection episodes in hemodialysis (HD) patients with ADPKD and the dialysis dose has not yet been fully elucidated. In this report, we describe a case of an HD patient with ADPKD that was provided elongation of HD time from 4-h twice weekly HD to 8-h thrice weekly nocturnal HD. As a result, the frequency of cyst infection episodes decreased from 10.0 to 1.5 days a month. Our findings suggest that prolonged HD time might contribute to amelioration of refractory cyst infections in patients with ADPKD.
    Keywords:  8-h Thrice weekly nocturnal hemodialysis; Autosomal dominant polycystic kidney disease (ADPKD); C-reactive protein; Hemodialysis product (HDP); Neutrophil/lymphocyte ratio (NLR); Renal cyst infection
    DOI:  https://doi.org/10.1007/s13730-021-00614-w
  3. Indian J Ophthalmol. 2021 Jul;69(7): 1735-1740
    Corneal endothelial cell density and microvascular changes of retina and optic disc in autosomal dominant polycystic kidney disease.
    Bengi Ece Kurtul, Ahmet Elbeyli, Ahmet Kakac, Faruk Turgut.
      Purpose: Vascular endothelial dysfunction in autosomal dominant polycystic kidney disease (ADPKD) may affect the retinal vascular parameters due to structural similarities of kidney and retina. We aimed to evaluate the microvascular changes of retina and optic disc and also corneal endothelial cell density in patients with ADPKD.Methods: Forty-six eyes of 23 patients with ADPKD (Group 1), and 46 eyes of 23 sex- and age-matched healthy controls (Group 2) were included in this cross-sectional study. Demographic and ophthalmic findings of participants were collected. Corneal endothelial cell density (CECD) measurements were obtained by noncontact specular microscopy. Foveal retinal thickness, peripapillary retinal nerve fiber layer (RNFL) thickness, vessel density in different sections of the retina and optic nerve head were analyzed by optical coherence tomography angiography.
    Results: The mean ages were 41 ± 11 years for Group 1 and 39 ± 10 years for Group 2 (P = 0.313). CECD values were significantly lower in group 1 when compared to group 2 (2653 ± 306 cells/mm2 and 2864 ± 244 cells/mm2, respectively, P < 0.001). The foveal retinal thickness and RNFL thickness were similar, but superior quadrant thickness of RNFL was significantly lower in Group 1 than Group 2 (126 ± 14 μm vs. 135 ± 15 μm, P = 0.003). In Group 1, whole image of optic disc radial peripapillary capillary densities were significantly lower compared to Group 2 (49.4 ± 2.04%, and 50.0 ± 2.2%, respectively, P = 0.043). There was no significant difference regarding superficial, deep retinal vessel densities, foveal avascular zone and flow areas between the groups (P > 0.05 for all).
    Conclusion: Lower CECD values and decreased superior quadrant RNFL thickness, and microvascular densities of optic disc were revealed in patients with ADPKD. Evaluation of CECD and retinal microvasculature may be helpful in the management of these patients.
    Keywords:  Cornea endothelial cell density; optic disc; optical coherence tomography angiography; polycystic kidney disease; retina; specular microscopy
    DOI:  https://doi.org/10.4103/ijo.IJO_3212_20
  4. Front Bioeng Biotechnol. 2021 ;9 624553
    A Multitubular Kidney-on-Chip to Decipher Pathophysiological Mechanisms in Renal Cystic Diseases.
    Sarah Myram, Bastien Venzac, Brice Lapin, Aude Battistella, Fanny Cayrac, Bertrand Cinquin, Charles Cavaniol, Giacomo Gropplero, Isabelle Bonnet, Sophie Demolombe, Stéphanie Descroix, Sylvie Coscoy.
      Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major renal pathology provoked by the deletion of PKD1 or PKD2 genes leading to local renal tubule dilation followed by the formation of numerous cysts, ending up with renal failure in adulthood. In vivo, renal tubules are tightly packed, so that dilating tubules and expanding cysts may have mechanical influence on adjacent tubules. To decipher the role of this coupling between adjacent tubules, we developed a kidney-on-chip reproducing parallel networks of tightly packed tubes. This original microdevice is composed of cylindrical hollow tubes of physiological dimensions, parallel and closely packed with 100-200 μm spacing, embedded in a collagen I matrix. These multitubular systems were properly colonized by different types of renal cells with long-term survival, up to 2 months. While no significant tube dilation over time was observed with Madin-Darby Canine Kidney (MDCK) cells, wild-type mouse proximal tubule (PCT) cells, or with PCT Pkd1 +/- cells (with only one functional Pkd1 allele), we observed a typical 1.5-fold increase in tube diameter with isogenic PCT Pkd1 -/- cells, an ADPKD cellular model. This tube dilation was associated with an increased cell proliferation, as well as a decrease in F-actin stress fibers density along the tube axis. With this kidney-on-chip model, we also observed that for larger tube spacing, PCT Pkd1 -/- tube deformations were not spatially correlated with adjacent tubes whereas for shorter spacing, tube deformations were increased between adjacent tubes. Our device reveals the interplay between tightly packed renal tubes, constituting a pioneering tool well-adapted to further study kidney pathophysiology.
    Keywords:  ADPKD; hydrogel; kidney-on-chip; microfabrication; tube deformation
    DOI:  https://doi.org/10.3389/fbioe.2021.624553
  5. Front Genet. 2021 ;12 642849
    Renal and Skeletal Anomalies in a Cohort of Individuals With Clinically Presumed Hereditary Nephropathy Analyzed by Molecular Genetic Testing.
    Michaela Stippel, Korbinian M Riedhammer, Bärbel Lange-Sperandio, Michaela Geßner, Matthias C Braunisch, Roman Günthner, Martin Bald, Miriam Schmidts, Peter Strotmann, Velibor Tasic, Christoph Schmaderer, Lutz Renders, Uwe Heemann, Julia Hoefele.
      Background: Chronic kidney disease (CKD) in childhood and adolescence occurs with a median incidence of 9 per million of the age-related population. Over 70% of CKD cases under the age of 25 years can be attributed to a hereditary kidney disease. Among these are hereditary podocytopathies, ciliopathies and (monogenic) congenital anomalies of the kidney and urinary tract (CAKUT). These disease entities can present with a vast variety of extrarenal manifestations. So far, skeletal anomalies (SA) have been infrequently described as extrarenal manifestation in these entities. The aim of this study was to retrospectively investigate a cohort of individuals with hereditary podocytopathies, ciliopathies or CAKUT, in which molecular genetic testing had been performed, for the extrarenal manifestation of SA. Material and Methods: A cohort of 65 unrelated individuals with a clinically presumed hereditary podocytopathy (focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome), ciliopathy (nephronophthisis, Bardet-Biedl syndrome, autosomal recessive/dominant polycystic kidney disease), or CAKUT was screened for SA. Data was acquired using a standardized questionnaire and medical reports. 57/65 (88%) of the index cases were analyzed using exome sequencing (ES). Results: 8/65 (12%) index individuals presented with a hereditary podocytopathy, ciliopathy, or CAKUT and an additional skeletal phenotype. In 5/8 families (63%), pathogenic variants in known disease-associated genes (1x BBS1, 1x MAFB, 2x PBX1, 1x SIX2) could be identified. Conclusions: This study highlights the genetic heterogeneity and clinical variability of hereditary nephropathies in respect of skeletal anomalies as extrarenal manifestation.
    Keywords:  CAKUT; FSGS; SRNS; ciliopathy; hereditary nephropathy; podocytopathy; skeletal anomaly
    DOI:  https://doi.org/10.3389/fgene.2021.642849
  6. Mol Genet Genomic Med. 2021 Jun 15. e1726
    Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus.
    Adam J Shapiro, Kimberley Kaspy, M Leigh Ann Daniels, Jaclyn R Stonebraker, Van-Hung Nguyen, Lyne Joyal, Michael R Knowles, Maimoona A Zariwala.
      BACKGROUND: Primary ciliary dyskinesia (PCD) is a mostly autosomal recessive, genetic disease of abnormal motile cilia function, resulting in bronchiectasis, infertility, organ laterality defects, and chronic otolaryngology disease. Though motile, ependymal cilia influencing cerebrospinal fluid flow in the central nervous system share many aspects of structure and function with motile cilia in the respiratory tract, hydrocephalus is rarely associated with PCD. Recently, pathogenic variants in FOXJ1 (Chr 17q25.1) were identified causing PCD associated with hydrocephalus, reduced respiratory cilia number, axonemal microtubule disorganization, and occurring in a de novo, autosomal dominant inheritance pattern.METHOD: Two patients with chronic oto-sino-pulmonary disease and hydrocephalus underwent candidate testing of FOXJ1. Coding region and splice junctions were sequenced and analyzed under the auspices of Genetic Disorders of Mucociliary Clearance Consortium.
    RESULTS: Upon sequencing of the entire coding region and splice-junctions, heterozygous, pathogenic variants in FOXJ1 were discovered in exon 3 of two patients: an 11-month-old female with situs inversus totalis (NM_001454.4: c.945delC (p.Phe315Leufs*18)) and a 51 year-old male, post-double lung transplantation (NM_001454.4: c.929_932delACTG (p.Asp310Glyfs*22)). FOXJ1 variants were not detected in the available parents and the siblings of these probands.
    CONCLUSION: FOXJ1 pathogenic variants cause PCD in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus. Physicians treating patients with hydrocephalus and chronic oto-sino-pulmonary disease should be aware of this PCD association and test for FOXJ1 variants.
    DOI:  https://doi.org/10.1002/mgg3.1726
  7. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Apr 25. 50(2): 245-260
    Primary cilium and its role in tumorigenesis.
    Yi Sun, Hongmei Mao.
      The primary cilium, a sensory organelle that protrudes from the surface of most eukaryotic cells, receives and transduces various critical signals that are essential for normal development and homeostasis. Structural or functional disruption of primary cilia causes a number of human diseases, including cancer. Primary cilia has cross talks with cell cycle and it may act as a cell cycle checkpoint to suppress cancer development. Moreover, primary cilia has cross-regulation with autophagy, which may affect tumor progression. We then discuss the association of the primary cilia with several oncogenic signaling pathways, including Shh, Wnt, Notch and platelet-derived growth factor receptor (PDGFR). Since these signaling pathways are often over-activated in many types of human cancers, primary cilia are likely to play a role in the tumorigenesis by modulating these pathways. Finally, we summarize current progress on the role of cilia during tumorigenesis and the challenges that the cilia-cancer field faces.
    Keywords:  Autophagy; Cell cycle; Cilia-related signaling pathways; Primary cilia; Tumorigenesis
    DOI:  https://doi.org/10.3724/zdxbyxb-2021-0048
  8. Small GTPases. 2021 Jun 17. 1-22
    Rho GTPases in kidney physiology and diseases.
    Steichen Clara, Herve Jean Claude, Hauet Thierry, Bourmeyster Nicolas.
      Rho family GTPases are molecular switches best known for their pivotal role in dynamic regulation of the actin cytoskeleton, but also of cellular morphology, motility, adhesion and proliferation. The prototypic members of this family (RhoA, Rac1 and Cdc42) also contribute to the normal kidney function and play important roles in the structure and function of various kidney cells including tubular epithelial cells, mesangial cells and podocytes. The kidney's vital filtration function depends on the structural integrity of the glomerulus, the proximal portion of the nephron. Within the glomerulus, the architecturally actin-based cytoskeleton podocyte forms the final cellular barrier to filtration. The glomerulus appears as a highly dynamic signalling hub that is capable of integrating intracellular cues from its individual structural components. Dynamic regulation of the podocyte cytoskeleton is required for efficient barrier function of the kidney. As master regulators of actin cytoskeletal dynamics, Rho GTPases are therefore of critical importance for sustained kidney barrier function. Dysregulated activities of the Rho GTPases and of their effectors are implicated in the pathogenesis of both hereditary and idiopathic forms of kidney diseases. Diabetic nephropathy is a progressive kidney disease that is caused by injury to kidney glomeruli. High glucose activates RhoA/Rho-kinase in mesangial cells, leading to excessive extracellular matrix production (glomerulosclerosis). This RhoA/Rho-kinase pathway also seems involved in the post-transplant hypertension frequently observed during treatment with calcineurin inhibitors, whereas Rac1 activation was observed in post-transplant ischaemic acute kidney injury.
    Keywords:  Rho GTPases; cytoskeletal dynamics; diabetes; nephropathies; podocytes
    DOI:  https://doi.org/10.1080/21541248.2021.1932402
  9. Biochem Biophys Res Commun. 2021 Jun 11. pii: S0006-291X(21)00933-5. [Epub ahead of print]566 164-169
    PEA prevented early BBB disruption after cerebral ischaemic/reperfusion (I/R) injury through regulation of ROCK/MLC signaling.
    Dequan Kong, Baoying Xie, Yuhang Li, Yaping Xu.
      Palmitoylethanolamide (PEA) offers a strong protection against BBB disruption and neurological deficits after cerebral ischaemic/reperfusion (I/R) injury. To date, these BBB protective effects of PEA are mainly attributed to PPARα-mediated actions. However, whether PEA protects against BBB disruption through direct regulation of cytoskeletal microfilaments remains unknown. Here, we identified PEA as a Rho-associated protein kinase (ROCK2) inhibitor (IC50 = 38.4 ± 4.8 μM). In vitro data suggested that PEA reduced the activation of ROCK/MLC signaling and stress fiber formation within microvascular endothelial cells (ECs) after oxygen-glucose deprivation (OGD), and consequently attenuated early (0-4 h) EC barrier disruption. These actions of PEA could not be blocked by the PPARα antagonist GW6471. In summary, the present study described a previously unexplored role of PEA as a ROCK2 inhibitor, and propose a PPARα-independent mechanism for pharmacological effects of PEA.
    Keywords:  Blood–brain barrier (BBB); Cerebral ischaemic; Myosin light chain (MLC); Palmitoylethanolamide (PEA); Reperfusion (I/R) injury; Rho-associated protein kinase (ROCK)
    DOI:  https://doi.org/10.1016/j.bbrc.2021.06.019
  10. J Cell Sci. 2021 Jun 15. pii: jcs247163. [Epub ahead of print]134(12):
    The structural basis of intraflagellar transport at a glance.
    Mareike A Jordan, Gaia Pigino.
      The intraflagellar transport (IFT) system is a remarkable molecular machine used by cells to assemble and maintain the cilium, a long organelle extending from eukaryotic cells that gives rise to motility, sensing and signaling. IFT plays a critical role in building the cilium by shuttling structural components and signaling receptors between the ciliary base and tip. To provide effective transport, IFT-A and IFT-B adaptor protein complexes assemble into highly repetitive polymers, called IFT trains, that are powered by the motors kinesin-2 and IFT-dynein to move bidirectionally along the microtubules. This dynamic system must be precisely regulated to shuttle different cargo proteins between the ciliary tip and base. In this Cell Science at a Glance article and the accompanying poster, we discuss the current structural and mechanistic understanding of IFT trains and how they function as macromolecular machines to assemble the structure of the cilium.
    Keywords:  Cilia; Dynein; IFT; Kinesin; Protein structure; Transport
    DOI:  https://doi.org/10.1242/jcs.247163
  11. Evid Based Complement Alternat Med. 2021 ;2021 6615615
    Mechanism of Yifei Decoction Combined with MitoQ on Inhibition of TGFβ1/NOX4 and PDGF/ROCK Signal Pathway in Idiopathic Pulmonary Fibrosis.
    Lijuan Chen, Chengzhong Lan, Hong Xiao, Xiaoli Zhang, Xiangrong Qi, Li Ouyang, Yanbin Yang, Fengying Wang, Qihua Jin, Yi Sun.
      Background: Rho-related coiled helix forming protein kinase (Rho-ROCK) and another important fibrogenic factor-PDGF play a critical role in collagen deposition in rat lung tissue. Yifei decoction (YFT), a Chinese herbal decoction, has been used to treat idiopathic pulmonary fibrosis (IPF) in clinical practice and has produced positive outcomes; however, convincing evidence is currently lacking. The present study aimed to investigate the effects of YFT combined with MitoQ in rats with IPF and to explore the underlying mechanism.Methods: Rat IPF model was established by endotracheal injection of 5 mg/kg BleomycinA5 into the specific pathogen-free SD rats. MitoQ (6.5 μmol/kg once daily), YFT (10 ml/kg once daily), and MitoQ + YFT (6.5 μmol/kg + 10 ml/kg once daily) were used to treat the rat model for 4 weeks, respectively. The normal rats without IPF were used as the controls. After 4 weeks of drug treatment, lung histopathology was assessed. Immunohistochemistry was used to detect the expression of fibronectin and collagen IV in lung tissue. The expression of IL-6, IL-1β, TNF-α, GSH-Px, SOD, MDA, and hydroxyproline was determined by enzyme-linked immunosorbent assay. The expressions of TGFβ1, NOX4, PDGFR-β, and ROCK1 were determined using real-time quantitative PCR and Western blot.
    Results: After 4 weeks of drug treatment, comparison of the MitoQ + YFT group with the IPF group showed that lung injury scores, W/D, lung tissue hydroxyproline, fibronectin, collagen IV content, and IL-6, IL-1β, TNF-α, and MDA levels were significantly lower (P < 0.05), as well as the expression of TGFβ1, NOX4, PDGFR-β, and ROCK1, but the activity of GSH-Px and SOD was higher (P < 0.05).
    Conclusion: MitoQ combined with YFT can improve lung injury in rats with pulmonary fibrosis by reducing the secretion of proinflammatory cytokines and inhibiting TGFβ1/NOX4 and PDGF/ROCK signaling pathways. It may provide a new method for the treatment of pulmonary fibrosis.
    DOI:  https://doi.org/10.1155/2021/6615615
  12. Methods. 2021 Jun 11. pii: S1046-2023(21)00159-6. [Epub ahead of print]
    Multi-dimensional and spatiotemporal correlative imaging at the plasma membrane of live cells to determine the continuum nano-to-micro scale lipid adaptation and collective motion.
    Miguel Bernabé-Rubio, Minerva Bosch-Fortea, Miguel A Alonso, Jorge Bernardino de la Serna.
      The primary cilium is a specialized plasma membrane protrusion with important receptors for signalling pathways. In polarized epithelial cells, the primary cilium assembles after the midbody remnant (MBR) encounters the centrosome at the apical surface. The membrane surrounding the MBR, namely remnant associated membrane patch (RAMP), once situated next to the centrosome, releases some of its lipid components to form a centrosome-associated membrane patch (CAMP) from which the ciliary membrane stems. The RAMP undergoes a spatiotemporal membrane refinement during the formation of the CAMP, which becomes highly enriched in condensed membranes with low lateral mobility. To better understand this process, we have developed a correlative imaging approach that yields quantitative information about the lipid lateral packing, its mobility and collective assembly at the plasma membrane at different spatial scales over time. Our work paves the way towards a quantitative understanding of the spatiotemporal lipid collective assembly at the plasma membrane as a functional determinant in cell biology and its direct correlation with the membrane physicochemical state. These findings allowed us to gain a deeper insight into the mechanisms behind the biogenesis of the ciliary membrane of polarized epithelial cells.
    DOI:  https://doi.org/10.1016/j.ymeth.2021.06.007
  13. Biol Rev Camb Philos Soc. 2021 Jun 15.
    Fine-tuning multiciliated cell differentiation at the post-transcriptional level: contribution of miR-34/449 family members.
    Ioannis Loukas, Margarita Skamnelou, Stavroula Tsaridou, Spyridoula Bournaka, Sokratis Grigoriadis, Stavros Taraviras, Zoi Lygerou, Marina Arbi.
      Cell differentiation is a process that must be precisely regulated for the maintenance of tissue homeostasis. Differentiation towards a multiciliated cell fate is characterized by well-defined stages, where a transcriptional cascade is activated leading to the formation of multiple centrioles and cilia. Centrioles migrate and dock to the apical cell surface and, acting as basal bodies, give rise to multiple motile cilia. The concerted movement of cilia ensures directional fluid flow across epithelia and defects either in their number or structure can lead to disease phenotypes. Micro-RNAs (miRNAs; miRs) are small, non-coding RNA molecules that play an important role in post-transcriptional regulation of gene expression. miR-34b/c and miR-449a/b/c specifically function throughout the differentiation of multiciliated cells, fine-tuning the expression of many different centriole- and cilia-related genes. They strictly regulate the expression levels of genes that are required both for commitment towards the multiciliated cell fate (e.g. Notch) and for the establishment and maintenance of this fate by regulating the expression of transcription factors and structural components of the pathway. Herein we review miR-34 and miR-449 spatiotemporal regulation along with their roles during the different stages of multiciliogenesis.
    Keywords:  cilia; miR-34; miR-449; micro-RNAs; multiciliated cell differentiation
    DOI:  https://doi.org/10.1111/brv.12755
  14. Development. 2021 Jun 01. pii: dev199232. [Epub ahead of print]148(11):
    Combinatorial patterns of graded RhoA activation and uniform F-actin depletion promote tissue curvature.
    Marlis Denk-Lobnig, Jan F Totz, Natalie C Heer, Jörn Dunkel, Adam C Martin.
      During development, gene expression regulates cell mechanics and shape to sculpt tissues. Epithelial folding proceeds through distinct cell shape changes that occur simultaneously in different regions of a tissue. Here, using quantitative imaging in Drosophila melanogaster, we investigate how patterned cell shape changes promote tissue bending during early embryogenesis. We find that the transcription factors Twist and Snail combinatorially regulate a multicellular pattern of lateral F-actin density that differs from the previously described Myosin-2 gradient. This F-actin pattern correlates with whether cells apically constrict, stretch or maintain their shape. We show that the Myosin-2 gradient and F-actin depletion do not depend on force transmission, suggesting that transcriptional activity is required to create these patterns. The Myosin-2 gradient width results from a gradient in RhoA activation that is refined through the balance between RhoGEF2 and the RhoGAP C-GAP. Our experimental results and simulations of a 3D elastic shell model show that tuning gradient width regulates tissue curvature.
    Keywords:   Drosophila ; Actomyosin; Morphogenesis; RhoGAP; RhoGEF; Tissue folding; Transcriptional patterning
    DOI:  https://doi.org/10.1242/dev.199232
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