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Your search keyword '"Steve D M, Brown"' showing total 7 results
Start Over Author "Steve D M, Brown" Journal nature communications
7 results on '"Steve D M, Brown"'

1. Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing

Author

Zane G. Moreland, Fangfang Jiang, Carlos Aguilar, Melanie Barzik, Rui Gong, Ghazaleh Behnammanesh, Jinho Park, Arik Shams, Christian Faaborg-Andersen, Jesse C. Werth, Randall Harley, Daniel C. Sutton, James B. Heidings, Stacey M. Cole, Andrew Parker, Susan Morse, Elizabeth Wilson, Yasuharu Takagi, James R. Sellers, Steve D. M. Brown, Thomas B. Friedman, Gregory M. Alushin, Michael R. Bowl, and Jonathan E. Bird

Subjects
Science
Abstract

Abstract Assembly of actin-based stereocilia is critical for cochlear hair cells to detect sound. To tune their mechanosensivity, stereocilia form bundles composed of graded rows of ascending height, necessitating the precise control of actin polymerization. Myosin 15 (MYO15A) drives hair bundle development by delivering critical proteins to growing stereocilia that regulate actin polymerization via an unknown mechanism. Here, we show that MYO15A is itself an actin nucleation-promoting factor. Moreover, a deafness-causing mutation in the MYO15A actin-binding interface inhibits nucleation activity but still preserves some movement on filaments in vitro and partial trafficking on stereocilia in vivo. Stereocilia fail to elongate correctly in this mutant mouse, providing evidence that MYO15A-driven actin nucleation contributes to hair bundle biogenesis. Our work shows that in addition to generating force and motility, the ATPase domain of MYO15A can directly regulate actin polymerization and that disrupting this activity can promote cytoskeletal disease, such as hearing loss.

Published
2025
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2. Improving laboratory animal genetic reporting: LAG-R guidelines

Author

Lydia Teboul, James Amos-Landgraf, Fernando J. Benavides, Marie-Christine Birling, Steve D. M. Brown, Elizabeth Bryda, Rosie Bunton-Stasyshyn, Hsian-Jean Chin, Martina Crispo, Fabien Delerue, Michael Dobbie, Craig L. Franklin, Ernst-Martin Fuchtbauer, Xiang Gao, Christelle Golzio, Rebecca Haffner, Yann Hérault, Martin Hrabe de Angelis, Kevin C. Kent Lloyd, Terry R. Magnuson, Lluis Montoliu, Stephen A. Murray, Ki-Hoan Nam, Lauryl M. J. Nutter, Eric Pailhoux, Fernando Pardo Manuel de Villena, Kevin Peterson, Laura Reinholdt, Radislav Sedlacek, Je Kyung Seong, Toshihiko Shiroishi, Cynthia Smith, Toru Takeo, Louise Tinsley, Jean-Luc Vilotte, Søren Warming, Sara Wells, C. Bruce Whitelaw, Atsushi Yoshiki, Asian Mouse Mutagenesis Resource Association, CELPHEDIA infrastructure, INFRAFRONTIER consortium, International Mammalian Genome Society, International Mouse Phenotyping Consortium, International Society for Transgenic Technologies, Mutant Mouse Resource and Research Centers, Phenomics Australia, RRRC- Rat Resource and Research Center, and Guillaume Pavlovic

Subjects
Science
Abstract

Abstract The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals’ genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.

Published
2024
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3. Human and mouse essentiality screens as a resource for disease gene discovery

Author

Pilar Cacheiro, Violeta Muñoz-Fuentes, Stephen A. Murray, Mary E. Dickinson, Maja Bucan, Lauryl M. J. Nutter, Kevin A. Peterson, Hamed Haselimashhadi, Ann M. Flenniken, Hugh Morgan, Henrik Westerberg, Tomasz Konopka, Chih-Wei Hsu, Audrey Christiansen, Denise G. Lanza, Arthur L. Beaudet, Jason D. Heaney, Helmut Fuchs, Valerie Gailus-Durner, Tania Sorg, Jan Prochazka, Vendula Novosadova, Christopher J. Lelliott, Hannah Wardle-Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedlacek, David J. Adams, John R. Seavitt, Glauco Tocchini-Valentini, Fabio Mammano, Robert E. Braun, Colin McKerlie, Yann Herault, Martin Hrabě de Angelis, Ann-Marie Mallon, K. C. Kent Lloyd, Steve D. M. Brown, Helen Parkinson, Terrence F. Meehan, Damian Smedley, The Genomics England Research Consortium, and The International Mouse Phenotyping Consortium

Subjects
Science
Abstract

Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Published
2020
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4. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Michael R. Bowl, Michelle M. Simon, Neil J. Ingham, Simon Greenaway, Luis Santos, Heather Cater, Sarah Taylor, Jeremy Mason, Natalja Kurbatova, Selina Pearson, Lynette R. Bower, Dave A. Clary, Hamid Meziane, Patrick Reilly, Osamu Minowa, Lois Kelsey, The International Mouse Phenotyping Consortium, Glauco P. Tocchini-Valentini, Xiang Gao, Allan Bradley, William C. Skarnes, Mark Moore, Arthur L. Beaudet, Monica J. Justice, John Seavitt, Mary E. Dickinson, Wolfgang Wurst, Martin Hrabe de Angelis, Yann Herault, Shigeharu Wakana, Lauryl M. J. Nutter, Ann M. Flenniken, Colin McKerlie, Stephen A. Murray, Karen L. Svenson, Robert E. Braun, David B. West, K. C. Kent Lloyd, David J. Adams, Jacqui White, Natasha Karp, Paul Flicek, Damian Smedley, Terrence F. Meehan, Helen E. Parkinson, Lydia M. Teboul, Sara Wells, Karen P. Steel, Ann-Marie Mallon, and Steve D. M. Brown

Subjects
Science
Abstract

The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017
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5. CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells

Author

Arnaud P. J. Giese, Yi-Quan Tang, Ghanshyam P. Sinha, Michael R. Bowl, Adam C. Goldring, Andrew Parker, Mary J. Freeman, Steve D. M. Brown, Saima Riazuddin, Robert Fettiplace, William R. Schafer, Gregory I. Frolenkov, and Zubair M. Ahmed

Subjects
Science
Abstract

Inner ear hair cells detect sound through deflection of stereocilia that harbor mechanically-gated channels. Here the authors show that protein responsible for Usher syndrome, CIB2, interacts with these channels and is essential for their function and hearing in mice.

Published
2017
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6. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

Author

Paul K. Potter, Michael R. Bowl, Prashanthini Jeyarajan, Laura Wisby, Andrew Blease, Michelle E. Goldsworthy, Michelle M. Simon, Simon Greenaway, Vincent Michel, Alun Barnard, Carlos Aguilar, Thomas Agnew, Gareth Banks, Andrew Blake, Lauren Chessum, Joanne Dorning, Sara Falcone, Laurence Goosey, Shelley Harris, Andy Haynes, Ines Heise, Rosie Hillier, Tertius Hough, Angela Hoslin, Marie Hutchison, Ruairidh King, Saumya Kumar, Heena V. Lad, Gemma Law, Robert E. MacLaren, Susan Morse, Thomas Nicol, Andrew Parker, Karen Pickford, Siddharth Sethi, Becky Starbuck, Femke Stelma, Michael Cheeseman, Sally H. Cross, Russell G. Foster, Ian J. Jackson, Stuart N. Peirson, Rajesh V. Thakker, Tonia Vincent, Cheryl Scudamore, Sara Wells, Aziz El-Amraoui, Christine Petit, Abraham Acevedo-Arozena, Patrick M. Nolan, Roger Cox, Anne-Marie Mallon, and Steve D. M. Brown

Subjects
Science
Abstract

Random mutagenesis can uncover novel genes involved in phenotypic traits. Here the authors perform a large-scale phenotypic screen on over 100 mouse strains generated by ENU mutagenesis to identify mice with age-related diseases, which they attribute to specific mutations revealed by whole-genome sequencing.

Published
2016
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7. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

Author

Carlos A. Aguilar, Becky Starbuck, Siddharth Sethi, Paul Potter, Gemma Law, Marie Hutchison, Ruairidh King, Gareth Banks, Anne-Marie Mallon, Ines Heise, Thomas Agnew, Vincent Michel, Rosie Hillier, Femke Stelma, Patrick M. Nolan, Aziz El-Amraoui, Michelle Simon, Laura Wisby, Shelley Harris, Susan Morse, Laurence Goosey, Ian J. Jackson, Steve D. M. Brown, Lauren Chessum, Michelle Goldsworthy, Robert E MacLaren, Saumya Kumar, Michael Cheeseman, Andrew Parker, Sara Wells, Christine Petit, Sally H. Cross, Cheryl L. Scudamore, Stuart N. Peirson, Simon Greenaway, Heena V. Lad, Rajesh V. Thakker, Prashanthini Jeyarajan, Abraham Acevedo-Arozena, Andrew Blake, Karen Pickford, Sara Falcone, T Nicol, Angela Hoslin, Andy Haynes, Alun R. Barnard, Tonia L. Vincent, Russell G. Foster, Tertius Hough, Joanne Dorning, Michael R. Bowl, Roger D. Cox, A Blease, MRC Harwell Institute [UK], Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, University of Edinburgh, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was funded by the Medical Research Council, UK, (primarily by reference MC U142684172 and partly by MC U142661184, MC U142684173, MC U142684175 and MC_PC_U127561112). The work was also partly funded by Arthritis Research UK Centre for Osteoarthritis Pathogenesis (A.B., T.V.), grant reference 20205, the BBSRC (S.N.P.), the EC—TREATRUSH (Health-F2-2010-242013), ERC advanced grant ‘Hair bundle’ (ERC-2011-AdG 294570), and a Wellcome Trust Strategic Award (098461/Z/12/Z) to the Sleep and Circadian Neuroscience Institute (SCNi) (R.G.F. and S.N.P.). We thank the High‐Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust, grant reference 090532/Z/09/Z and MRC Hub grant G0900747 91070) for the generation of the sequencing data., European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), and European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012)

Subjects
0301 basic medicine, Male, Aging, Phenotypic screening, [SDV]Life Sciences [q-bio], Science, ved/biology.organism_classification_rank.species, Mutant, General Physics and Astronomy, Mutagenesis (molecular biology technique), Biology, General Biochemistry, Genetics and Molecular Biology, Epithelium, Article, 03 medical and health sciences, Hearing, medicine, Evoked Potentials, Auditory, Brain Stem, Animals, Genetic Testing, Model organism, Gene, Genetic testing, Genetics, Multidisciplinary, medicine.diagnostic_test, ved/biology, General Chemistry, Phenotype, Cochlea, Pedigree, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Mutagenesis, Mutation, Female, Genetic screen
Abstract

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss., Random mutagenesis can uncover novel genes involved in phenotypic traits. Here the authors perform a large-scale phenotypic screen on over 100 mouse strains generated by ENU mutagenesis to identify mice with age-related diseases, which they attribute to specific mutations revealed by whole-genome sequencing.

Published
2016
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