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1. Shaping the future of kidney genetics in Australia: proceedings from the KidGen policy implementation workshop 2023

Author

Mallawaarachchi, Amali, Biros, Erik, Harris, Trudie, Bennetts, Bruce, Boughtwood, Tiffany, Elliott, Justine, Fowles, Lindsay, Gardos, Robert, Garza, Denisse, Goranitis, Ilias, Haas, Matilda, Huntley, Vanessa, Jefferis, Julia, Kassahn, Karin, Leaver, Anna, Lundie, Ben, Lunke, Sebastian, O’Connor, Caitlin, Pratt, Greg, Quinlan, Catherine, Shearman, Dianne, Soraru, Jacqueline, Sundaram, Madhivanan, Tchan, Michel, Valente, Giulia, White, Julie, Wilkins, Ella, Alexander, Steve I., Amir, Noa, Best, Stephanie, Gul, Hossai, Jayasinghe, Kushani, McCarthy, Hugh, Patel, Chirag, Stark, Zornitza, and Mallett, Andrew J.

Published
2024
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3. A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship

Author

Ades, Lesley, Enriquez, Annabel, McLean, Alison, Smyth, Renee, Alankarage, Dimithu, Fatkin, Diane, McNamara, James, Soka, Magdalena, Morgan almog, Fear, Vanessa, Medi, Caroline, Stark, Zornitza, Al-Shinnag, Mohammad, Fine, Miriam, Metke, Alejandro, Sy, Raymond, Atherton, John J., Finlay, Keri, Milnes, Di, Tang, Dotti, Austin, Rachel, Garza, Denisse, Milward, Michael, Taylor, Jessica, Bagnall, Richard D., Giannoulatou, Eleni, Morrish, Ansley, Taylor, Shelby, Barnett, Chris, Gongolidis, Laura, Morwood, Jim, Tchan, Michel, Blue, Gillian M., Gray, Belinda, Mountain, Helen, Thompson, Tina, Bodek, Simon, Greer, Cassie, Mowat, David, Thorpe, Jordan, Boggs, Kirsten, Haan, Eric, Ng, Chai-Ann, Trainer, Alison, Bogwitz, Michael, Haas, Mathilda, Nowak, Natalie, Trivedi, Gunjan, Boughtwood, Tiffany, Hanna, Bernadette, Martinez, Noelia Nunez, Valente, Giulia, Bray, Alessandra, Harvey, Richard, Ohanian, Monique, van Spaendonck-Zwarts, Karin, Brion, Marie-Jo, Hayward, Janette, O’Sullivan, Sinead, Vandenberg, Jamie, Brown, Jaye, Herrera, Carmen, Overkov, Angela, Verma, Kunal, Richardson, Rob Bryson, Hill, Adam, Pachter, Nicholas, Vidgen, Miranda, Burnett, Leslie, Hollingsworth, Georgie, Patel, Chirag, Vohra, Jitendra, Burns, Charlotte, Hollway, Georgina, Perrin, Mark, Waddel-Smith, Kathryn, Cao, Michelle, Horton, Ari E., Perry, Matthew, Wallis, Mathew, Carr, Will, Howting, Denise, Pflaumer, Andreas, Weintraub, Robert G., Casauria, Sarah, Ingles, Jodie, Phillips, Peta, Wilson, Meredith, Chalinor, Heather, Isbister, Joanne, Phuong, Thuan, Winlaw, David, Chang, Yuchen, Jackson, Matilda, Pope-Couston, Rachel, Worgan, Lisa, Chapman, Gavin, James, Paul, Poplawski, Nicola K., Wornham, Linda, Charitou, Theosodia, Jane-Pantaleo, Sarah, Punni, Preeti, Wu, Kathy, Chong, Belinda, Johnson, Renee, Quinn, Michael C.J., Yeates, Laura, Collins, Felicity, Kelly, Andrew, Quinn, Michael, Zentner, Dominica, Correnti, Gemma, King-Smith, Sarah, Rajagopalan, Sulekha, Cox, Kathy, Kirk, Edwin, Raju, Hariharan, Cunningham, Fiona, Kummerfeld, Sarah, Rath, Emma M., Das, Debjani, Lassman, Timo, Regan, Matthew, Davis, Jason, Lipton, Jonathon, Rogers, Jonathan, Davis, Andrew, Lunke, Sebastian, Ryan, Mark, De Fazio, Paul, Macciocca, Ivan, Sandaradura, Sarah, de Silva, Michelle, MacIntyre, Paul, Schonrock, Nicole, Den Elzen, Nicola, Madelli, Evanthia O., Scuffham, Paul, Devery, Sophie, Mallawaarachchi, Amali, Semsarian, Chris, Dobbins, Julia, Mansour, Julia, Sherburn, Isabella, Dunwoodie, Sally L., Martin, Ellenore, Sherlock, Mary-Clare, Dwyer, Nathan, Mathew, Jacob, Singer, Emma, Elbracht-Leong, Stefanie, Mattiske, Tessa, Smerdon, Carla, Elliott, David, McGaughran, Julie, Smith, Janine, Brown, Jaye S., Haas, Matilda, and Pantaleo, Sarah-Jane

Published
2024
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5. Future-proofing genomic data and consent management: a comprehensive review of technology innovations

Author

Oliva, Adrien, primary, Kaphle, Anubhav, additional, Reguant, Roc, additional, Sng, Letitia M F, additional, Twine, Natalie A, additional, Malakar, Yuwan, additional, Wickramarachchi, Anuradha, additional, Keller, Marcel, additional, Ranbaduge, Thilina, additional, Chan, Eva K F, additional, Breen, James, additional, Buckberry, Sam, additional, Guennewig, Boris, additional, Haas, Matilda, additional, Brown, Alex, additional, Cowley, Mark J, additional, Thorne, Natalie, additional, Jain, Yatish, additional, and Bauer, Denis C, additional

Published
2024
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6. Dynamic Consent : An Evaluation and Reporting Framework

Author

Prictor, Megan, Lewis, Megan A., Newson, Ainsley J., Haas, Matilda, Baba, Sachiko, Kim, Hannah, Kokado, Minori, Minari, Jusaku, Molnár-Gábor, Fruzsina, Yamamoto, Beverley, Kaye, Jane, and Teare, Harriet J. A.

Published
2020

10. Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare

Author

Stark, Zornitza, primary, Boughtwood, Tiffany, additional, Haas, Matilda, additional, Braithwaite, Jeffrey, additional, Gaff, Clara L., additional, Goranitis, Ilias, additional, Spurdle, Amanda B., additional, Hansen, David P., additional, Hofmann, Oliver, additional, Laing, Nigel, additional, Metcalfe, Sylvia, additional, Newson, Ainsley J., additional, Scott, Hamish S., additional, Thorne, Natalie, additional, Ward, Robyn L., additional, Dinger, Marcel E., additional, Best, Stephanie, additional, Long, Janet C., additional, Grimmond, Sean M., additional, Pearson, John, additional, Waddell, Nicola, additional, Barnett, Christopher P., additional, Cook, Matthew, additional, Field, Michael, additional, Fielding, David, additional, Fox, Stephen B., additional, Gecz, Jozef, additional, Jaffe, Adam, additional, Leventer, Richard J., additional, Lockhart, Paul J., additional, Lunke, Sebastian, additional, Mallett, Andrew J., additional, McGaughran, Julie, additional, Mileshkin, Linda, additional, Nones, Katia, additional, Roscioli, Tony, additional, Scheffer, Ingrid E., additional, Semsarian, Christopher, additional, Simons, Cas, additional, Thomas, David M., additional, Thorburn, David R., additional, Tothill, Richard, additional, White, Deborah, additional, Dunwoodie, Sally, additional, Simpson, Peter T., additional, Phillips, Peta, additional, Brion, Marie-Jo, additional, Finlay, Keri, additional, Quinn, Michael CJ., additional, Mattiske, Tessa, additional, Tudini, Emma, additional, Boggs, Kirsten, additional, Murray, Sean, additional, Wells, Kathy, additional, Cannings, John, additional, Sinclair, Andrew H., additional, Christodoulou, John, additional, and North, Kathryn N., additional

Published
2023
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12. Two-way engagement and communication strategies for health and medical research participants: a rapid evidence review

Author

Brown, Rosie and Haas, Matilda

Subjects
two-way communication, evaluation, event, dynamic consent, clinical trial, registry, health and medical research, two-way engagement
Abstract

This project is seeking to determine what two-way engagement and communication strategies have been trialled in health and medical research context. It focuses on implementations that have been evaluated, and what the outcomes were for participants and research projects.

Published
2023
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18. Dynamic Consent: An Evaluation and Reporting Framework

Author

Prictor, Megan, primary, Lewis, Megan A., additional, Newson, Ainsley J., additional, Haas, Matilda, additional, Baba, Sachiko, additional, Kim, Hannah, additional, Kokado, Minori, additional, Minari, Jusaku, additional, Molnár-Gábor, Fruzsina, additional, Yamamoto, Beverley, additional, Kaye, Jane, additional, and Teare, Harriet J. A., additional

Published
2019
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20. The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses.

Author

Rius, Rocio, Compton, Alison G., Baker, Naomi L., Balasubramaniam, Shanti, Best, Stephanie, Bhattacharya, Kaustuv, Boggs, Kirsten, Boughtwood, Tiffany, Braithwaite, Jeffrey, Bratkovic, Drago, Bray, Alessandra, Brion, Marie-Jo, Burke, Jo, Casauria, Sarah, Chong, Belinda, Coman, David, Cowie, Shannon, Cowley, Mark, de Silva, Michelle G., Delatycki, Martin B., Edwards, Samantha, Ellaway, Carolyn, Fahey, Michael C., Finlay, Keri, Fletcher, Janice, Frajman, Leah E., Frazier, Ann E., Gayevskiy, Velimir, Ghaoui, Roula, Goel, Himanshu, Goranitis, Ilias, Haas, Matilda, Hock, Daniella H., Howting, Denise, Jackson, Matilda R., Kava, Maina P., Kemp, Madonna, King-Smith, Sarah, Lake, Nicole J., Lamont, Phillipa J., Lee, Joy, Long, Janet C., MacShane, Mandi, Madelli, Evanthia O., Martin, Ellenore M., Marum, Justine E., Mattiske, Tessa, McGill, Jim, Metke, Alejandro, Murray, Sean, Panetta, Julie, Phillips, Liza K., Quinn, Michael C.J., Ryan, Michael T., Schenscher, Sarah, Simons, Cas, Smith, Nicholas, Stroud, David A., Tchan, Michel C., Tom, Melanie, Wallis, Mathew, Ware, Tyson L., Welch, AnneMarie E., Wools, Christine, Wu, You, Christodoulou, John, and Thorburn, David R.

Abstract

Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.

Published
2024
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21. The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome

Author

Li, Shan Shan, primary, Qu, Zhengdong, additional, Haas, Matilda, additional, Ngo, Linh, additional, Heo, You Jeong, additional, Kang, Hyo Jung, additional, Britto, Joanne Maria, additional, Cullen, Hayley Daniella, additional, Vanyai, Hannah Kate, additional, Tan, Seong-Seng, additional, Chan-Ling, Tailoi, additional, Gunnersen, Jenny Margaret, additional, and Heng, Julian Ik-Tsen, additional

Published
2016
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22. De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation

Author

Haas, Matilda A., primary, Ngo, Linh, additional, Li, Shan Shan, additional, Schleich, Sibylle, additional, Qu, Zhengdong, additional, Vanyai, Hannah K., additional, Cullen, Hayley D., additional, Cardona-Alberich, Aida, additional, Gladwyn-Ng, Ivan E., additional, Pagnamenta, Alistair T., additional, Taylor, Jenny C., additional, Stewart, Helen, additional, Kini, Usha, additional, Duncan, Kent E., additional, Teleman, Aurelio A., additional, Keays, David A., additional, and Heng, Julian I.-T., additional

Published
2016
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24. Visualization and Genetic Manipulation of Dendrites and Spines in the Mouse Cerebral Cortex and Hippocampus using In utero Electroporation

Author

Pacary, Emilie, Haas, Matilda A, Wildner, Hendrik, Azzarelli, Roberta, Bell, Donald M, Abrous, Djoher Nora, and Guillemot, François

Subjects
Cerebral Cortex, Animals, Dendrites, Electroporation, Embryo, Mammalian, Hippocampus, Mice, hippocampus, Mammalian, spines, dendrite, Embryo, Neuronal development, gain and loss of function, Molecular Biology, In utero electroporation, Neuroscience, Issue 65, Developmental Biology
Abstract

In utero electroporation (IUE) has become a powerful technique to study the development of different regions of the embryonic nervous system (1-5). To date this tool has been widely used to study the regulation of cellular proliferation, differentiation and neuronal migration especially in the developing cerebral cortex (6-8). Here we detail our protocol to electroporate in utero the cerebral cortex and the hippocampus and provide evidence that this approach can be used to study dendrites and spines in these two cerebral regions. Visualization and manipulation of neurons in primary cultures have contributed to a better understanding of the processes involved in dendrite, spine and synapse development. However neurons growing in vitro are not exposed to all the physiological cues that can affect dendrite and/or spine formation and maintenance during normal development. Our knowledge of dendrite and spine structures in vivo in wild-type or mutant mice comes mostly from observations using the Golgi-Cox method( 9). However, Golgi staining is considered to be unpredictable. Indeed, groups of nerve cells and fiber tracts are labeled randomly, with particular areas often appearing completely stained while adjacent areas are devoid of staining. Recent studies have shown that IUE of fluorescent constructs represents an attractive alternative method to study dendrites, spines as well as synapses in mutant / wild-type mice (10-11) (Figure 1A). Moreover in comparison to the generation of mouse knockouts, IUE represents a rapid approach to perform gain and loss of function studies in specific population of cells during a specific time window. In addition, IUE has been successfully used with inducible gene expression or inducible RNAi approaches to refine the temporal control over the expression of a gene or shRNA (12). These advantages of IUE have thus opened new dimensions to study the effect of gene expression/suppression on dendrites and spines not only in specific cerebral structures (Figure 1B) but also at a specific time point of development (Figure 1C). Finally, IUE provides a useful tool to identify functional interactions between genes involved in dendrite, spine and/or synapse development. Indeed, in contrast to other gene transfer methods such as virus, it is straightforward to combine multiple RNAi or transgenes in the same population of cells. In summary, IUE is a powerful method that has already contributed to the characterization of molecular mechanisms underlying brain function and disease and it should also be useful in the study of dendrites and spines.

Published
2012

25. Behavioral and other phenotypes in a cytoplasmic Dynein light intermediate chain 1 mutant mouse

Author

Banks, Gareth T, Haas, Matilda A, Line, Samantha, Shepherd, Hazel L, AlQatari, Mona, Stewart, Sammy, Rishal, Ida, Philpott, Amelia, Hafezparast, Majid, and others

Abstract

The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown from in vivo studies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system.

Published
2011

26. 14-3-3ζ deficient mice in the BALB/c background display behavioural and anatomical defects associated with neurodevelopmental disorders

Author

Xu, Xiangjun, primary, Jaehne, Emily J., additional, Greenberg, Zarina, additional, McCarthy, Peter, additional, Saleh, Eiman, additional, Parish, Clare L., additional, Camera, Daria, additional, Heng, Julian, additional, Haas, Matilda, additional, Baune, Bernhard T., additional, Ratnayake, Udani, additional, Buuse, Maarten van den, additional, Lopez, Angel F., additional, Ramshaw, Hayley S., additional, and Schwarz, Quenten, additional

Published
2015
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29. Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities

Author

Breuss, Martin, primary, Heng, Julian Ik-Tsen, additional, Poirier, Karine, additional, Tian, Guoling, additional, Jaglin, Xavier Hubert, additional, Qu, Zhengdong, additional, Braun, Andreas, additional, Gstrein, Thomas, additional, Ngo, Linh, additional, Haas, Matilda, additional, Bahi-Buisson, Nadia, additional, Moutard, Marie-Laure, additional, Passemard, Sandrine, additional, Verloes, Alain, additional, Gressens, Pierre, additional, Xie, Yunli, additional, Robson, Kathryn J.H., additional, Rani, Deepa Selvi, additional, Thangaraj, Kumarasamy, additional, Clausen, Tim, additional, Chelly, Jamel, additional, Cowan, Nicholas Justin, additional, and Keays, David Anthony, additional

Published
2012
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30. What is in a name? Justifying terminology for genomic findings beyond the initial test indication: A scoping review

Author

White, Stephanie, Haas, Matilda, Laginha, Kitty-Jean, Laurendet, Kirsten, Gaff, Clara, Vears, Danya, and Newson, Ainsley J.

Abstract

Genome sequencing can generate findings beyond the initial test indication that may be relevant to a patient or research participant’s health. In the decade since the American College of Medical Genetics and Genomics published its recommendations for reporting these findings, consensus regarding terminology has remained elusive and a variety of terms are in use globally. We conducted a scoping review to explore terminology choice and the justifications underlying those choices. Documents were included if they contained a justification for their choice of term(s) related to findings beyond the initial genomic test indication. From 3571 unique documents, 52 were included, just over half of which pertained to the clinical context (n = 29, 56%). We identified 4 inter-related concepts used to defend or oppose terms: expectedness of the finding, effective communication, relatedness to the original test indication, and how genomic information was generated. A variety of justifications were used to oppose the term “incidental,” whereas “secondary” has broader support as a term to describe findings deliberately sought. Terminology choice would benefit from further work to include the views of patients. We contend that clear definitions will improve ethical debate and support communication about genomic findings beyond the initial test indication.

Published
2023
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34. Mutations in the β-Tubulin Gene TUBB5Cause Microcephaly with Structural Brain Abnormalities

Author

Breuss, Martin, Heng, Julian Ik-Tsen, Poirier, Karine, Tian, Guoling, Jaglin, Xavier Hubert, Qu, Zhengdong, Braun, Andreas, Gstrein, Thomas, Ngo, Linh, Haas, Matilda, Bahi-Buisson, Nadia, Moutard, Marie-Laure, Passemard, Sandrine, Verloes, Alain, Gressens, Pierre, Xie, Yunli, Robson, Kathryn J.H., Rani, Deepa Selvi, Thangaraj, Kumarasamy, Clausen, Tim, Chelly, Jamel, Cowan, Nicholas Justin, and Keays, David Anthony

Abstract

The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5(M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5in embryonic neurogenesis and microcephaly.

Published
2012
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36. Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare

Author

Zornitza Stark, Tiffany Boughtwood, Matilda Haas, Jeffrey Braithwaite, Clara L. Gaff, Ilias Goranitis, Amanda B. Spurdle, David P. Hansen, Oliver Hofmann, Nigel Laing, Sylvia Metcalfe, Ainsley J. Newson, Hamish S. Scott, Natalie Thorne, Robyn L. Ward, Marcel E. Dinger, Stephanie Best, Janet C. Long, Sean M. Grimmond, John Pearson, Nicola Waddell, Christopher P. Barnett, Matthew Cook, Michael Field, David Fielding, Stephen B. Fox, Jozef Gecz, Adam Jaffe, Richard J. Leventer, Paul J. Lockhart, Sebastian Lunke, Andrew J. Mallett, Julie McGaughran, Linda Mileshkin, Katia Nones, Tony Roscioli, Ingrid E. Scheffer, Christopher Semsarian, Cas Simons, David M. Thomas, David R. Thorburn, Richard Tothill, Deborah White, Sally Dunwoodie, Peter T. Simpson, Peta Phillips, Marie-Jo Brion, Keri Finlay, Michael CJ. Quinn, Tessa Mattiske, Emma Tudini, Kirsten Boggs, Sean Murray, Kathy Wells, John Cannings, Andrew H. Sinclair, John Christodoulou, Kathryn N. North, Stark, Zornitza, Boughtwood, Tiffany, Haas, Matilda, Braithwaite, Jeffrey, Scott, Hamish S, and North, Kathryn N

Subjects
Genetics, Genetics (clinical)
Abstract

Refereed/Peer-reviewed Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Published
2023

37. 14-3-3ζ deficient mice in the BALB/c background display behavioural and anatomical defects associated with neurodevelopmental disorders

Author

Clare L. Parish, Quenten Schwarz, Xiangjun Xu, Peter McCarthy, Matilda Haas, Eiman Saleh, Julian Ik-Tsen Heng, Bernhard T. Baune, Zarina Greenberg, Hayley S. Ramshaw, Angel F. Lopez, Emily J. Jaehne, Maarten van den Buuse, Udani Ratnayake, Daria Camera, Xu, Xiangjun, Jaehne, Emily J, Greenberg, Zarina, McCarthy, Peter, Saleh, Eiman, Parish, Clare L, Camera, Daria, Heng, Julian, Haas, Matilda, Baune, Bernhard T, Ratnayake, Udani, Van den Buuse, Maarten, Lopez, Angel F, Ramshaw, Hayley S, and Schwarz, Quenten

Subjects
Male, Dopamine, 14-3-3 zeta, Congenic, Gene Expression, Hippocampus, Hippocampal formation, Article, BALB/c, Mice, Lateral ventricles, Lateral Ventricles, medicine, Animals, Maze Learning, Spatial Memory, Dopamine transporter, Mice, Knockout, cognitive defects, Dopamine Plasma Membrane Transport Proteins, Mice, Inbred BALB C, Multidisciplinary, biology, neurodevelopmental disorders, Pyramidal Cells, epistatic interactions, biology.organism_classification, Disease Models, Animal, 14-3-3 Proteins, Mossy Fibers, Hippocampal, Immunology, Knockout mouse, Schizophrenia, biology.protein, Female, Neuroscience, Signal Transduction, medicine.drug
Abstract

Sequencing and expression analyses implicate 14-3-3ζ as a genetic risk factor for neurodevelopmental disorders such as schizophrenia and autism. In support of this notion, we recently found that 14-3-3ζ−/− mice in the Sv/129 background display schizophrenia-like defects. As epistatic interactions play a significant role in disease pathogenesis we generated a new congenic strain in the BALB/c background to determine the impact of genetic interactions on the 14-3-3ζ−/− phenotype. In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ−/− BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippocampus. In contrast to our previous analyses, 14-3-3ζ−/− BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling. Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippocampus and ventricle and cognitive defects such as hippocampal-dependent learning and memory.

Published
2015

38. Behavioral and other phenotypes in a cytoplasmic Dynein light intermediate chain 1 mutant mouse.

Author

Banks GT, Haas MA, Line S, Shepherd HL, Alqatari M, Stewart S, Rishal I, Philpott A, Kalmar B, Kuta A, Groves M, Parkinson N, Acevedo-Arozena A, Brandner S, Bannerman D, Greensmith L, Hafezparast M, Koltzenburg M, Deacon R, Fainzilber M, and Fisher EM

Subjects
Animals, Animals, Newborn, Asparagine genetics, Cell Count methods, Cells, Cultured, Cerebral Cortex cytology, Dendrites genetics, Embryo, Mammalian, Female, Fibroblasts physiology, Fibroblasts ultrastructure, Ganglia, Spinal cytology, Green Fluorescent Proteins genetics, Male, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity genetics, Nerve Tissue Proteins, Neural Conduction genetics, Neurons classification, Neurons cytology, Neurons physiology, Protein Transport drug effects, Protein Transport genetics, Psychomotor Performance, Statistics, Nonparametric, Tyrosine genetics, Weight Lifting physiology, Behavior, Animal physiology, Cytoplasmic Dyneins genetics, Gene Expression Regulation, Developmental genetics, Phenotype, Point Mutation genetics
Abstract

The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown from in vivo studies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system.

Published
2011
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39. Rho kinase activates ezrin-radixin-moesin (ERM) proteins and mediates their function in cortical neuron growth, morphology and motility in vitro.

Author

Haas MA, Vickers JC, and Dickson TC

Subjects
Animals, Axons drug effects, Blotting, Western methods, Cell Movement drug effects, Cell Proliferation drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Embryo, Mammalian, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Immunohistochemistry methods, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Microtubule-Associated Proteins metabolism, Neuroblastoma, Neurons drug effects, Phosphoproteins metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors, Pseudopodia drug effects, Rats, Rats, Wistar, Time Factors, Tubulin metabolism, rho-Associated Kinases, Cell Enlargement drug effects, Cell Movement physiology, Cerebral Cortex cytology, DNA-Binding Proteins metabolism, Intracellular Signaling Peptides and Proteins physiology, Neurons cytology, Protein Serine-Threonine Kinases physiology, Transcription Factors metabolism
Abstract

The ezrin-radixin-moesin (ERM) family of proteins contribute to cytoskeletal processes underlying many vital cellular functions. Their previously elucidated roles in non-neuronal cells are an indication of their potential importance in CNS neurons. The specific mechanisms of their activation are unknown, but are likely to depend on factors such as the cell type and biological context. For ERM proteins to become active they must be phosphorylated at a specific C-terminal threonine residue. In non-neuronal cells, several kinases, including the Rho GTPase family member Rho kinase, have been identified as capable of phosphorylating the C-terminal threonine. In these experiments we have investigated specifically the potential role of Rho kinase mediated ERM activation in cortical neurons, utilizing a new pharmacologic inhibitor of Rho kinase and quantitative analysis of aspects of neuronal functions potentially mediated by ERM proteins. Rho kinase inhibition significantly suppressed aspects of neuronal development including neurite initiation and outgrowth, as well as growth cone morphology, with a concomitant loss of phosphorylated ERM immunolabeling in areas associated with neuronal growth. The ability of the Rho kinase inhibitor to decrease the amount of pERM protein was shown by immunoblotting. Post-injury responses were negatively affected by Rho kinase inhibition, namely by a significant decrease in the number of regenerative neurites. We investigated a novel role for ERM proteins in neuron migration using a post-injury motility assay, where Rho kinase inhibition resulted in significant and drastic reduction in neuron motility and phosphorylated ERM immunolabeling. Thus, Rho kinase is an important activator of ERMs in mediating specific neuronal functions.

Published
2007
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