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Mariko Takahara, Yohei Katoh, Kentaro Nakamura, Tomoaki Hirano, Maho Sugawa, Yuta Tsurumi, Kazuhisa Nakayama
The intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes mediates ciliary protein trafficking. Mutations in the genes encoding the six subunits of the IFT-A complex (IFT43, IFT121, IFT122, IFT139, IFT140, and IFT144) are known to cause skeletal ciliopathies, including cranioectodermal dysplasia (CED). As the IFT122 subunit connects the core and peripheral subcomplexes of the IFT-A complex, it is expected to play a pivotal role in the complex. Indeed, we here showed that knockout (KO) of the IFT122 gene in hTERT-RPE1 cells using the CRISPR/Cas9 system led to a severe ciliogenesis defect, whereas KO of other IFT-A genes had minor effects on ciliogenesis but impaired ciliary protein trafficking...
February 1, 2018: Human Molecular Genetics
Tomoaki Hirano, Yohei Katoh, Kazuhisa Nakayama
Cilia serve as cellular antennae where proteins involved in sensory and developmental signaling, including G protein-coupled receptors (GPCRs), are specifically localized. Intraflagellar transport (IFT)-A and -B complexes mediate retrograde and anterograde ciliary protein trafficking, respectively. Using a visible immunoprecipitation assay to detect protein-protein interactions, we show that the IFT-A complex is divided into a core subcomplex, composed of IFT122/IFT140/IFT144, which is associated with TULP3, and a peripheral subcomplex, composed of IFT43/IFT121/IFT139, where IFT139 is most distally located...
February 1, 2017: Molecular Biology of the Cell
Su-Ren Chen, Yi-Xun Liu
Testis cords, embryonic precursors of the seminiferous tubules, are fundamental for testis structure and function. Delay or disruption of testis cord formation could result in gonadal dysgenesis. Although mechanisms regulating testis cord formation during sex determination have been well-studied, the genes and signaling pathways involving in testis cord maintenance after the cords have formed are not well characterized. It is now clear that the maintenance of cord structure is an active process. In this review, we summarize the recent findings regarding the regulation of testis cord integrity by a series of Sertoli cell transcription factors, including the WT1-SOX8/SOX9-beta-CATENIN-DHH network, GPR56, STIM1, and NR0B1 (also known as DAX1)...
February 2016: Biology of Reproduction
Shahida Moosa, Maria Gabriela Obregon, Janine Altmüller, Holger Thiele, Peter Nürnberg, Virginia Fano, Bernd Wollnik
Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive ciliary chondrodysplasia characterized by a recognizable craniofacial gestalt, skeletal abnormalities, and ectodermal features. To date, four genes have been shown to underlie the syndrome, namely, IFT122 (WDR10), WDR35 (IFT121), IFT43 (C14orf179), and WDR19 (IFT144). Clinical characterization of a larger cohort of patients with CED has been undertaken previously. Nevertheless, there are too few molecularly confirmed patients reported in the literature to determine precise genotype-phenotype correlations...
May 2016: American Journal of Medical Genetics. Part A
Elanor N Wainwright, Terje Svingen, Ee Ting Ng, Carol Wicking, Peter Koopman
The issues of whether and how some organs coordinate their size and shape with the blueprint of the embryo axis, while others appear to regulate their morphogenesis autonomously, remain poorly understood. Mutations in Ift144, encoding a component of the trafficking machinery of primary cilia assembly, result in a range of embryo patterning defects, affecting the limbs, skeleton and neural system. Here, we show that embryos of the mouse mutant Ift144(twt) develop gonads that are larger than wild-type. Investigation of the early patterning of the urogenital ridge revealed that the anterior-posterior domain of the gonad/mesonephros was extended at 10...
November 15, 2014: Developmental Biology
Henry Fehrenbach, Christian Decker, Tobias Eisenberger, Valeska Frank, Tobias Hampel, Ulrike Walden, Kerstin U Amann, Ingrid Krüger-Stollfuß, Hanno J Bolz, Karsten Häffner, Martin Pohl, Carsten Bergmann
BACKGROUND: An emerging number of clinically and genetically heterogeneous diseases now collectively termed ciliopathies have been connected to the dysfunction of primary cilia. We describe an 8-year-old girl with a complex phenotype that did not clearly match any familiar syndrome. CASE-DIAGNOSIS/TREATMENT: Hypotonia, facial dysmorphism and retardation were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure...
August 2014: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Karel F Liem, Alyson Ashe, Mu He, Peter Satir, Jennifer Moran, David Beier, Carol Wicking, Kathryn V Anderson
Two intraflagellar transport (IFT) complexes, IFT-A and IFT-B, build and maintain primary cilia and are required for activity of the Sonic hedgehog (Shh) pathway. A weak allele of the IFT-A gene, Ift144, caused subtle defects in cilia structure and ectopic activation of the Shh pathway. In contrast, strong loss of IFT-A, caused by either absence of Ift144 or mutations in two IFT-A genes, blocked normal ciliogenesis and decreased Shh signaling. In strong IFT-A mutants, the Shh pathway proteins Gli2, Sufu, and Kif7 localized correctly to cilia tips, suggesting that these pathway components were trafficked by IFT-B...
June 11, 2012: Journal of Cell Biology
Alyson Ashe, Natalie C Butterfield, Liam Town, Andrew D Courtney, Ashley N Cooper, Charles Ferguson, Rachael Barry, Fredrik Olsson, Karel F Liem, Robert G Parton, Brandon J Wainwright, Kathryn V Anderson, Emma Whitelaw, Carol Wicking
Mutations in components of the intraflagellar transport (IFT) machinery required for assembly and function of the primary cilium cause a subset of human ciliopathies characterized primarily by skeletal dysplasia. Recently, mutations in the IFT-A gene IFT144 have been described in patients with Sensenbrenner and Jeune syndromes, which are associated with short ribs and limbs, polydactyly and craniofacial defects. Here, we describe an N-ethyl-N-nitrosourea-derived mouse mutant with a hypomorphic missense mutation in the Ift144 gene...
April 15, 2012: Human Molecular Genetics
Robert H Behal, Mark S Miller, Hongmin Qin, Ben F Lucker, Alexis Jones, Douglas G Cole
Chlamydomonas reinhardtii intraflagellar transport (IFT) particles can be biochemically resolved into two smaller assemblies, complexes A and B, that contain up to six and 15 protein subunits, respectively. We provide here the proteomic and immunological analyses that verify the identity of all six Chlamydomonas A proteins. Using sucrose density gradient centrifugation and antibody pulldowns, we show that all six A subunits are associated in a 16 S complex in both the cell bodies and flagella. A significant fraction of the cell body IFT43, however, exhibits a much slower sedimentation of ∼2 S and is not associated with the IFT A complex...
April 6, 2012: Journal of Biological Chemistry
Cecilie Bredrup, Sophie Saunier, Machteld M Oud, Torunn Fiskerstrand, Alexander Hoischen, Damien Brackman, Sabine M Leh, Marit Midtbø, Emilie Filhol, Christine Bole-Feysot, Patrick Nitschké, Christian Gilissen, Olav H Haugen, Jan-Stephan F Sanders, Irene Stolte-Dijkstra, Dorus A Mans, Eric J Steenbergen, Ben C J Hamel, Marie Matignon, Rolph Pfundt, Cécile Jeanpierre, Helge Boman, Eyvind Rødahl, Joris A Veltman, Per M Knappskog, Nine V A M Knoers, Ronald Roepman, Heleen H Arts
A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy...
November 11, 2011: American Journal of Human Genetics
Shana M Williamson, David A Silva, Elizabeth Richey, Hongmin Qin
Mediating the transport of flagellar precursors and removal of turnover products, intraflagellar transport (IFT) is required for flagella assembly and maintenance. The IFT apparatus is composed of the anterograde IFT motor kinesin II, the retrograde IFT motor IFT-dynein, and IFT particles containing two complexes, A and B. In order to have a balanced two-way transportation, IFT-dynein has to be carried into flagella and transported to the flagellar tip by kinesin II, where it is activated to drive the retrograde IFT back to the flagellar base...
July 2012: Protoplasma
Peter N Inglis, Oliver E Blacque, Michel R Leroux
The nematode Caenorhabditis elegans presents numerous advantages for the identification and molecular analysis of intraflagellar transport (IFT)-associated proteins, which play a critical role in the formation of cilia. Many proteins were first described as participating in IFT in this organism, including IFTA-1 (IFT121), DYF-1 (fleer/IFT70), DYF-2 (IFT144), DYF-3 (Qilin), DYF-11 (MIP-T3/IFT54), DYF-13, XBX-1 (dynein light intermediate chain), XBX-2 (dynein light chain), CHE-13 (IFT57/HIPPI), orthologs of Bardet-Biedl syndrome proteins, and potential regulatory protein, IFTA-2 (RABL5/IFT22)...
2009: Methods in Cell Biology
Carlo Iomini, Linya Li, Jessica M Esparza, Susan K Dutcher
The intraflagellar transport machinery is required for the assembly of cilia. It has been investigated by biochemical, genetic, and computational methods that have identified at least 21 proteins that assemble into two subcomplexes. It has been hypothesized that complex A is required for retrograde transport. Temperature-sensitive mutations in FLA15 and FLA17 show defects in retrograde intraflagellar transport (IFT) in Chlamydomonas. We show that IFT144 and IFT139, two complex A proteins, are encoded by FLA15 and FLA17, respectively...
November 2009: Genetics
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