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Anna Hegsted, Forrest A Wright, SarahBeth Votra, David Pruyne
Formins are regulators of actin filament dynamics. We demonstrate here that two formins, FHOD-1 and EXC-6, are important in the nematode Caenorhabditis elegans for ovulation, during which actomyosin contractions push a maturing oocyte from the gonad arm into a distensible bag-like organ, the spermatheca. EXC-6, a homolog of the disease-associated mammalian formin INF2, is highly expressed in the spermatheca, where it localizes to cell-cell junctions and to circumferential actin filament bundles. Loss of EXC-6 does not noticeably affect the organization the actin filament bundles, and causes only a very modest increase in the population of junction-associated actin filaments...
October 22, 2016: Cytoskeleton
Johannes Münch, Maik Grohmann, Tom H Lindner, Carsten Bergmann, Jan Halbritter
BACKGROUND: Patients on renal replacement therapy are often unaware of their underlying condition and hence suffer from so-called end-stage renal disease (ESRD) of unknown origin. However, an exact diagnosis is not only important for better estimating the prognosis, but also when preparing for kidney transplantation. Whilst patients with FSGS without a confirmed genetic cause have a high recurrence rate in the transplanted organ, patients with a mutation generally exhibit no recurrence and have a good prognosis...
October 12, 2016: BMC Medical Genetics
Daniel D Shaye, Iva Greenwald
The C. elegans excretory cell (EC) is a powerful model for tubulogenesis, a conserved process that requires precise cytoskeletal regulation. EXC-6, an ortholog of the disease-associated formin INF2, coordinates cell outgrowth and lumen formation during EC tubulogenesis by regulating F-actin at the tip of the growing canal and the dynamics of basolateral microtubules. EXC-6 functions in parallel to EXC-5/FGD, a predicted activator of the Rho GTPase Cdc42. Here we identify the parallel pathway: EXC-5 functions through CDC-42 to regulate two other formins: INFT-2, another INF2 ortholog, and CYK-1, the sole ortholog of mammalian Diaphanous (mDia)...
October 3, 2016: Development
Maija Suvanto, Jaakko Patrakka, Timo Jahnukainen, Pia-Maria Sjöström, Matti Nuutinen, Pekka Arikoski, Janne Kataja, Marjo Kestilä, Hannu Jalanko
BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS. METHODS: We analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease...
August 29, 2016: Clinical and Experimental Nephrology
Balajikarthick Subramanian, Hua Sun, Paul Yan, Victoria T Charoonratana, Henry N Higgs, Fang Wang, Ka-Man V Lai, David M Valenzuela, Elizabeth J Brown, Johannes S Schlöndorff, Martin R Pollak
Mutations in the INF2 (inverted formin 2) gene, encoding a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause human focal segmental glomerulosclerosis (FSGS). INF2 interacts directly with certain other mammalian diaphanous formin proteins (mDia) that function as RhoA effector molecules. FSGS-causing INF2 mutations impair these interactions and disrupt the ability of INF2 to regulate Rho/Dia-mediated actin dynamics in vitro. However, the precise mechanisms by which INF2 regulates and INF2 mutations impair glomerular structure and function remain unknown...
August 2016: Kidney International
Friederike Werheid, Hamid Azzedine, Eva Zwerenz, Ahmet Bozkurt, Marcus J Moeller, Lilian Lin, Michael Mull, Martin Häusler, Jörg B Schulz, Joachim Weis, Kristl G Claeys
INTRODUCTION: Charcot-Marie-Tooth neuropathy (CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur. METHODS: We studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision. RESULTS: Patients harbored a PMP22 gene alteration (n = 28) or a mutation in MPZ (n = 11), GJB1 (n = 4), LITAF (n = 2), MFN2 (n = 2), INF2 (n = 1), NEFL (n = 1)...
April 2016: Brain and Behavior
Francesca Bartolini, Laura Andres-Delgado, Xiaoyi Qu, Sara Nik, Nagendran Ramalingam, Lenor Kremer, Miguel A Alonso, Gregg G Gundersen
Multiple formins regulate microtubule (MT) arrays, but whether they function individually or in a common pathway is unknown. Lysophosphatidic acid (LPA) stimulates the formation of stabilized detyrosinated MTs (Glu MTs) in NIH3T3 fibroblasts through RhoA and the formin mDia1. Here we show that another formin, INF2, is necessary for mDia1-mediated induction of Glu MTs and regulation of MT dynamics and that mDia1 can be bypassed by activating INF2. INF2 localized to MTs after LPA treatment in an mDia1-dependent manner, suggesting that mDia1 regulates INF2...
June 1, 2016: Molecular Biology of the Cell
I M Rood, E M H F Bongers, D Lugtenberg, I H H T Klein, E J Steenbergen, J F M Wetzels, J K J Deegens
Focal segmental glomerulosclerosis (FSGS) is one of the most common patterns of glomerular injury. FSGS can be caused by mutations in genes encoding proteins that play key roles in the function of the podocyte and glomerular basement membrane. In this case report we present a family with FSGS initially suspected to be Alport syndrome. Genetic analysis according to the Dutch guidelines of FSGS revealed a mutation in INF2.
February 2016: Netherlands Journal of Medicine
Ruth Rollason, Matthew Wherlock, Jenny A Heath, Kate J Heesom, Moin A Saleem, Gavin I Welsh
Focal segmental glomerulosclerosis (FSGS) is a devastating form of nephrotic syndrome which ultimately leads to end stage renal failure (ESRF). Mutations in inverted formin 2 (INF2), a member of the formin family of actin-regulating proteins, have recently been associated with a familial cause of nephrotic syndrome characterized by FSGS. INF2 is a unique formin that can both polymerize and depolymerize actin filaments. How mutations in INF2 lead to disease is unknown. In the present study, we show that three mutations associated with FSGS, E184K, S186P and R218Q, reduce INF2 auto-inhibition and increase association with monomeric actin...
2016: Bioscience Reports
Linda Panzer, Leona Trübe, Matthias Klose, Ben Joosten, Johan Slotman, Alessandra Cambi, Stefan Linder
Podosomes are actin-rich adhesion structures that depend on Arp2/3-complex-based actin nucleation. We now report the identification of the formins FHOD1 and INF2 as novel components and additional actin-based regulators of podosomes in primary human macrophages. FHOD1 surrounds the podosome core and is also present at podosome-connecting cables, whereas INF2 localizes at the podosome cap structure. Using a variety of microscopy-based methods; including a semiautomated podosome reformation assay, measurement of podosome oscillations, FRAP analysis of single podosomes, and structured illumination microscopy, both formins were found to regulate different aspects of podosome-associated contractility, with FHOD1 mediating actomyosin contractility between podosomes, and INF2 regulating contractile events at individual podosomes...
January 15, 2016: Journal of Cell Science
Wei-ke Ji, Anna L Hatch, Ronald A Merrill, Stefan Strack, Henry N Higgs
While the dynamin GTPase Drp1 plays a critical role during mitochondrial fission, mechanisms controlling its recruitment to fission sites are unclear. A current assumption is that cytosolic Drp1 is recruited directly to fission sites immediately prior to fission. Using live-cell microscopy, we find evidence for a different model, progressive maturation of Drp1 oligomers on mitochondria through incorporation of smaller mitochondrially-bound Drp1 units. Maturation of a stable Drp1 oligomer does not forcibly lead to fission...
November 26, 2015: ELife
Xiaowei Shao, Keiko Kawauchi, G V Shivashankar, Alexander D Bershadsky
The formin family proteins are important regulators of actin polymerization that are involved in many cellular processes. However, little is known about their specific cellular localizations. Here, we show that Diaphanous-related formin-3 (mDia2) localizes to the cytoplasmic side of the nuclear envelope. This localization of mDia2 to the nuclear rim required the presence of a nuclear localization signal (NLS) sequence at the mDia2 N-terminal. Consistent with this result, super-resolution images demonstrated that at the nuclear rim, mDia2 co-localized with the nuclear pore complexes and a nuclear transport receptor, importin β...
2015: Biology Open
Hiroshi Tamura, Hitoshi Nakazato, Shohei Kuraoka, Kaori Yoneda, Wataru Takahashi, Fumio Endo
AIM: Mutations of the inverted formin 2 gene (INF2), which encodes a member of the formin family, cause autosomal dominant focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth (CMT) disease-associated FSGS. However, their role in idiopathic FSGS remains unclear. This study investigated INF2 localization in the normal adult kidney and its expression in children with idiopathic nephrotic syndrome. METHODS: We generated a rabbit polyclonal antibody against the conjugated peptide from human INF2 and studied the glomerular expression of INF2 and synaptopodin using normal human adult kidney tissues and tissues from children with glomerular diseases such as minimal change disease (MCD), FSGS, IgA nephropathy (IgAN), non-IgA mesangial proliferative glomerulonephritis (non-IgAN), and Henoch-Schönlein purpura nephritis (HSPN)...
June 2016: Nephrology
Uri Manor, Sadie Bartholomew, Gonen Golani, Eric Christenson, Michael Kozlov, Henry Higgs, James Spudich, Jennifer Lippincott-Schwartz
Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER...
2015: ELife
Ying Maggie Chen, Helen Liapis
Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2. This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme. It also recounts recent recommendations for clinical management of FSGS based on translational studies and clinical trials. The advent of next-generation sequencing promises to provide nephrologists with rapid and novel approaches for the diagnosis and treatment of FSGS...
2015: BMC Nephrology
Pinar S Gurel, Mu A, Bingqian Guo, Rui Shu, Dale F Mierke, Henry N Higgs
INF2 (inverted formin 2) is a formin protein with unique biochemical effects on actin. In addition to the common formin ability to accelerate actin nucleation and elongation, INF2 can also sever filaments and accelerate their depolymerization. Although we understand key attributes of INF2-mediated severing, we do not understand the mechanism by which INF2 accelerates depolymerization subsequent to severing. Here, we show that INF2 can create short filaments (<60 nm) that continuously turn over actin subunits through a combination of barbed end elongation, severing, and WH2 motif-mediated depolymerization...
September 11, 2015: Journal of Biological Chemistry
(no author information available yet)
No abstract text is available yet for this article.
August 2015: Nature Reviews. Nephrology
Hua Sun, Khaldoun I Al-Romaih, Calum A MacRae, Martin R Pollak
Mutations in Inverted Formin 2 (INF2), a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth Disease (CMT) in humans. In addition to directly remodeling actin filaments in vitro, we have shown that INF2 regulates intracellular actin dynamics and actin dependent cellular behavior by opposing Rhoa/Dia signaling. As a step towards a better understanding of the human kidney disease, we wanted to explore the relevance of these findings to the in vivo situation...
December 2014: EBioMedicine
Dana M Blumberg, Elizabeth Dale, Noelle Pensec, George A Cioffi, Nathan Radcliffe, Michelle Pham, Lama Al-Aswad, Margaret Reynolds, Adam Ciarleglio
PURPOSE: To create a multivariable predictive model for glaucoma in an exclusively African American population and to compare the performance of the model with individual structural parameters derived from SD-OCT. PATIENTS AND METHODS: A total of 103 healthy eyes and 118 glaucomatous eyes of African American patients underwent SD-OCT optic disc and macular scanning. Twenty-seven optic nerve head, retinal nerve fiber layer (RNFL), and ganglion cell parameters were collected...
March 2016: Journal of Glaucoma
Jingyuan Xie, Xu Hao, Evren U Azeloglu, Hong Ren, Zhaohui Wang, Jun Ma, Jian Liu, Xiaodan Ma, Weiming Wang, Xiaoxia Pan, Wen Zhang, Fang Zhong, Yifu Li, Guoyu Meng, Krzysztof Kiryluk, John Cijiang He, Ali G Gharavi, Nan Chen
Here, we report a genetic study of an extended family of Chinese ancestry with focal segmental glomerulosclerosis (FSGS), with one of the affected members also concurrently diagnosed with IgA nephropathy (IgAN). By genome-wide linkage analysis and subsequent sequencing, we identified an S85W mutation in the inverted formin 2 (INF2) gene that perfectly cosegregated with the kidney disease phenotype. The entire INF2 coding region was sequenced in 200 healthy controls, 55 families with FSGS, and 34 families with IgAN...
September 2015: Kidney International
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