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2. A Standardized Nomenclature Design for Systematic Referencing and Identification of Animal Cellular Material.

Author

Schrade, Lisa, Mah, Nancy, Bandrowski, Anita, Chen, Ying, Dewender, Johannes, Diecke, Sebastian, Hiepen, Christian, Lancaster, Madeline, Marques-Bonet, Tomas, Martinez, Sira, Mueller, Sabine, Navara, Christopher, Prigione, Alessandro, Seltmann, Stefanie, Sochacki, Jaroslaw, Sutcliffe, Magdalena, Zywitza, Vera, Hildebrandt, Thomas, and Kurtz, Andreas

Subjects
FAIR data, biodiversity, biosample nomenclature, cryobanking, species conservation, standardization, unambiguous identifier, viable cell material, wildlife
Abstract

The documentation, preservation and rescue of biological diversity increasingly uses living biological samples. Persistent associations between species, biosamples, such as tissues and cell lines, and the accompanying data are indispensable for using, exchanging and benefiting from these valuable materials. Explicit authentication of such biosamples by assigning unique and robust identifiers is therefore required to allow for unambiguous referencing, avoid identification conflicts and maintain reproducibility in research. A predefined nomenclature based on uniform rules would facilitate this process. However, such a nomenclature is currently lacking for animal biological material. We here present a first, standardized, human-readable nomenclature design, which is sufficient to generate unique and stable identifying names for animal cellular material with a focus on wildlife species. A species-specific human- and machine-readable syntax is included in the proposed standard naming scheme, allowing for the traceability of donated material and cultured cells, as well as data FAIRification. Only when it is consistently applied in the public domain, as publications and inter-institutional samples and data are exchanged, distributed and stored centrally, can the risks of misidentification and loss of traceability be mitigated. This innovative globally applicable identification system provides a standard for a sustainable structure for the long-term storage of animal bio-samples in cryobanks and hence facilitates current as well as future species conservation and biomedical research.

Published
2024

4. How human-derived brain organoids are built differently from brain organoids derived of genetically-close relatives: A multi-scale hypothesis

Author

Zhang, Tao, Gupta, Sarthak, Lancaster, Madeline A., and Schwarz, J. M.

Subjects
Quantitative Biology - Tissues and Organs, Condensed Matter - Soft Condensed Matter
Abstract

How genes affect tissue scale organization remains a longstanding biological puzzle. As experimental efforts are underway to solve this puzzle via quantification of gene expression and sub-cellular, cellular and tissue structure, computational efforts remain far behind. To potentially help accelerate the computational efforts, we review two recent publications, the first on a cellular-based model for tissues and the second on a cell nucleus model consisting of chromatin and a lamina shell. We then give a perspective on how the two models can be combined to test multiscale hypotheses linking the chromatin scale and the tissue scale. To be concrete, we turn to an in vitro system for the brain known as a brain organoid. We provide a multiscale hypothesis to distinguish structural differences between brain organoids built from induced-pluripotent human stem cells and from induced-pluripotent gorilla and chimpanzee stem cells. Recent experiments discover that a cell fate transition from neuroepithelial cells to radial glial cells includes a new intermediate state that is delayed in human-derived brain organoids as compared to their genetically-close relatives, which significantly narrows and lengthens the cells on the apical side [1]. Additional experiments revealed that the protein ZEB2 plays a major role in the emergence of this new intermediate state with ZEB2 mRNA levels peaking at the onset of the emergence [1]. We postulate that the enhancement of ZEB2 expression driving this intermediate state is potentially due to chromatin reorganization. More precisely, there exists critical strain triggering the reorganization that is higher for human-derived stem cells, thereby resulting in a delay. Such a hypothesis can readily be tested experimentally within individual cells and within brain organoids as well as computationally to work towards solving the gene-to-tissue organization puzzle., Comment: 13 pages, 8 figures

Published
2023

5. Using Organoids to Model Sex Differences in the Human Brain

Author

Baron-Cohen, Simon, Allison, Carrie, Warrier, Varun, Tsompanidis, Alex, Adhya, Dwaipayan, Holt, Rosie, Smith, Paula, Parsons, Tracey, Davis, Joanna, Hassall, Matthew, Geschwind, Daniel H., Heazell, Alexander EP., Mill, Jonathan, Franklin, Alice, Bamford, Rosie, Davies, Jonathan, Hurles, Matthew E., Martin, Hilary C., Mousa, Mahmoud, Rowitch, David H., Niakan, Kathy K., Burton, Graham J., Ghafari, Fateneh, Srivastava, Deepak P., Dutan-Polit, Lucia, Pavlinek, Adam, Lancaster, Madeline A., Chiaradia, Ilaria, Biron-Shental, Tal, Gabis, Lidia V., Vernon, Anthony C., and Lancaster, Madeline

Published
2024
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7. MEA-NAP: A flexible network analysis pipeline for neuronal 2D and 3D organoid multielectrode recordings

Author

Sit, Timothy P.H., Feord, Rachael C., Dunn, Alexander W.E., Chabros, Jeremi, Oluigbo, David, Smith, Hugo H., Burn, Lance, Chang, Elise, Boschi, Alessio, Yuan, Yin, Gibbons, George M., Khayat-Khoei, Mahsa, De Angelis, Francesco, Hemberg, Erik, Hemberg, Martin, Lancaster, Madeline A., Lakatos, Andras, Eglen, Stephen J., Paulsen, Ole, and Mierau, Susanna B.

Published
2024
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8. A nomenclature consensus for nervous system organoids and assembloids.

Author

Pașca, Sergiu, Arlotta, Paola, Camp, J, Cappello, Silvia, Gage, Fred, Knoblich, Jürgen, Park, In-Hyun, Reiner, Orly, Song, Hongjun, Studer, Lorenz, Temple, Sally, Testa, Giuseppe, Treutlein, Barbara, Vaccarino, Flora, Lancaster, Madeline, Ming, Guo-Li, Kriegstein, Arnold, Muotri, Alysson, and Bateup, Helen

Subjects
Consensus, Humans, Models, Biological, Nervous System, Organoids, Pluripotent Stem Cells, Terminology as Topic
Abstract

Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants.

Published
2022

9. Changing the public perception of human embryology

Author

Rivron, Nicolas C., Martinez-Arias, Alfonso, Sermon, Karen, Mummery, Christine, Schöler, Hans R., Wells, James, Nichols, Jenny, Hadjantonakis, Anna-Katerina, Lancaster, Madeline A., Moris, Naomi, Fu, Jianping, Sturmey, Roger G., Niakan, Kathy, Rossant, Janet, and Kato, Kazuto

Published
2023
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10. Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes

Author

Warrier, Varun, Stauffer, Eva-Maria, Huang, Qin Qin, Wigdor, Emilie M., Slob, Eric A. W., Seidlitz, Jakob, Ronan, Lisa, Valk, Sofie L., Mallard, Travis T., Grotzinger, Andrew D., Romero-Garcia, Rafael, Baron-Cohen, Simon, Geschwind, Daniel H., Lancaster, Madeline A., Murray, Graham K., Gandal, Michael J., Alexander-Bloch, Aaron, Won, Hyejung, Martin, Hilary C., Bullmore, Edward T., and Bethlehem, Richard A. I.

Published
2023
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11. Author Correction: CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Author

de Thonel, Aurélie, Ahlskog, Johanna K., Daupin, Kevin, Dubreuil, Véronique, Berthelet, Jérémy, Chaput, Carole, Pires, Geoffrey, Leonetti, Camille, Abane, Ryma, Barris, Lluís Cordón, Leray, Isabelle, Aalto, Anna L., Naceri, Sarah, Cordonnier, Marine, Benasolo, Carène, Sanial, Matthieu, Duchateau, Agathe, Vihervaara, Anniina, Puustinen, Mikael C., Miozzo, Federico, Fergelot, Patricia, Lebigot, Élise, Verloes, Alain, Gressens, Pierre, Lacombe, Didier, Gobbo, Jessica, Garrido, Carmen, Westerheide, Sandy D., David, Laurent, Petitjean, Michel, Taboureau, Olivier, Rodrigues-Lima, Fernando, Passemard, Sandrine, Sabéran-Djoneidi, Délara, Nguyen, Laurent, Lancaster, Madeline, Sistonen, Lea, and Mezger, Valérie

Published
2023
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15. ISSCR standards for the use of human stem cells in basic research

Author

Ludwig, Tenneille E., Andrews, Peter W., Barbaric, Ivana, Benvenisty, Nissim, Bhattacharyya, Anita, Crook, Jeremy M., Daheron, Laurence M., Draper, Jonathan S., Healy, Lyn E., Huch, Meritxell, Inamdar, Maneesha S., Jensen, Kim B., Kurtz, Andreas, Lancaster, Madeline A., Liberali, Prisca, Lutolf, Matthias P., Mummery, Christine L., Pera, Martin F., Sato, Yoji, Shimasaki, Noriko, Smith, Austin G., Song, Jihwan, Spits, Claudia, Stacey, Glyn, Wells, Christine A., Zhao, Tongbiao, and Mosher, Jack T.

Published
2023
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17. Voices in methods development.

Author

Anikeeva, Polina, Boyden, Edward, Brangwynne, Clifford, Cissé, Ibrahim I, Fiehn, Oliver, Fromme, Petra, Gingras, Anne-Claude, Greene, Casey S, Heard, Edith, Hell, Stefan W, Hillman, Elizabeth, Jensen, Grant Jay, Karchin, Rachel, Kiessling, Laura L, Kleinstiver, Benjamin P, Knight, Rob, Kukura, Philipp, Lancaster, Madeline A, Loman, Nicholas, Looger, Loren, Lundberg, Emma, Luo, Qingming, Miyawaki, Atsushi, Myers, Eugene W, Nolan, Garry P, Picotti, Paola, Reik, Wolf, Sauer, Markus, Shalek, Alex K, Shendure, Jay, Slavov, Nikolai, Tanay, Amos, Troyanskaya, Olga, van Valen, David, Wang, Hong-Wei, Yi, Chengqi, Yin, Peng, Zernicka-Goetz, Magdalena, and Zhuang, Xiaowei

Subjects
Biological Sciences, Technology, Medical and Health Sciences, Developmental Biology
Abstract

To mark the 15th anniversary of Nature Methods, we asked scientists from across diverse fields of basic biology research for their views on the most exciting and essential methodological challenges that their communities are poised to tackle in the near future.

Published
2019

19. Pluripotent stem cell‐derived organoids: A brief history of curiosity‐led discoveries.

Author

Lancaster, Madeline A.

Subjects
*PLURIPOTENT stem cells, *HUMAN biology, *EMBRYOLOGY, *MORPHOGENESIS, *TISSUE engineering
Abstract

Organoids are quickly becoming an accepted model for understanding human biology and disease. Pluripotent stem cells (PSC) provide a starting point for many organs and enable modeling of the embryonic development and maturation of such organs. The foundation of PSC‐derived organoids can be found in elegant developmental studies demonstrating the remarkable ability of immature cells to undergo histogenesis even when taken out of the embryo context. PSC‐organoids are an evolution of earlier methods such as embryoid bodies, taken to a new level with finer control and in some cases going beyond tissue histogenesis to organ‐like morphogenesis. But many of the discoveries that led to organoids were not necessarily planned, but rather the result of inquisitive minds with freedom to explore. Protecting such curiosity‐led research through flexible funding will be important going forward if we are to see further ground‐breaking discoveries. [ABSTRACT FROM AUTHOR]

Published
2024
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21. CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Author

de Thonel, Aurélie, Ahlskog, Johanna K., Daupin, Kevin, Dubreuil, Véronique, Berthelet, Jérémy, Chaput, Carole, Pires, Geoffrey, Leonetti, Camille, Abane, Ryma, Barris, Lluís Cordón, Leray, Isabelle, Aalto, Anna L., Naceri, Sarah, Cordonnier, Marine, Benasolo, Carène, Sanial, Matthieu, Duchateau, Agathe, Vihervaara, Anniina, Puustinen, Mikael C., Miozzo, Federico, Fergelot, Patricia, Lebigot, Élise, Verloes, Alain, Gressens, Pierre, Lacombe, Didier, Gobbo, Jessica, Garrido, Carmen, Westerheide, Sandy D., David, Laurent, Petitjean, Michel, Taboureau, Olivier, Rodrigues-Lima, Fernando, Passemard, Sandrine, Sabéran-Djoneidi, Délara, Nguyen, Laurent, Lancaster, Madeline, Sistonen, Lea, and Mezger, Valérie

Published
2022
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22. Using organoids to model sex differences in the human brain

Author

Pavlinek, Adam, primary, Adhya, Dwaipayan, additional, Tsompanidis, Alex, additional, Warrier, Varun, additional, Vernon, Anthony C., additional, Lancaster, Madeline, additional, Mill, Jonathan, additional, Srivastava, Deepak P., additional, and Baron-Cohen, Simon, additional

Published
2024
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24. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids

Author

Marsee, Ary, Roos, Floris, Verstegen, Monique, Clevers, Hans, Vallier, Ludovic, Takebe, Takanori, Huch, Meritxell, Peng, Weng Chuan, Forbes, Stuart, Lemaigre, Frédéric, de Koning, Eelco, Gehart, Helmuth, van der Laan, Luc, Spee, Bart, Boj, Sylvia, Baptista, Pedro, Schneeberger, Kerstin, Soroka, Carol, Heim, Markus, Nuciforo, Sandro, Zaret, Kenneth, Saito, Yoshimasa, Lutolf, Matthias, Cardinale, Vincenzo, Simons, Ben, van IJzendoorn, Sven, Kamiya, Akihide, Chikada, Hiromi, Wang, Shuyong, Mun, Seon Ju, Son, Myung Jin, Onder, Tamer Tevfik, Boyer, James, Sato, Toshiro, Georgakopoulos, Nikitas, Meneses, Andre, Broutier, Laura, Boulter, Luke, Grün, Dominic, IJzermans, Jan, Artegiani, Benedetta, van Boxtel, Ruben, Kuijk, Ewart, Carpino, Guido, Peltz, Gary, Banales, Jesus, Man, Nancy, Aloia, Luigi, LaRusso, Nicholas, George, Gregory, Rimland, Casey, Yeoh, George, Grappin-Botton, Anne, Stange, Daniel, Prior, Nicole, Tirnitz-Parker, Janina E.E., Andersson, Emma, Braconi, Chiara, Hannan, Nicholas, Lu, Wei-Yu, Strom, Stephen, Sancho-Bru, Pau, Ogawa, Shinichiro, Corbo, Vincenzo, Lancaster, Madeline, Hu, Huili, Fuchs, Sabine, Hendriks, Delilah, Roos, Floris J.M., Verstegen, Monique M.A., Forbes, Stuart J., and van der Laan, Luc J.W.

Published
2021
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25. Non-model model organisms

Author

Russell, James J, Theriot, Julie A, Sood, Pranidhi, Marshall, Wallace F, Landweber, Laura F, Fritz-Laylin, Lillian, Polka, Jessica K, Oliferenko, Snezhana, Gerbich, Therese, Gladfelter, Amy, Umen, James, Bezanilla, Magdalena, Lancaster, Madeline A, He, Shuonan, Gibson, Matthew C, Goldstein, Bob, Tanaka, Elly M, Hu, Chi-Kuo, and Brunet, Anne

Subjects
Biological Sciences, Ecology, Animals, Biology, Eukaryota, Models, Animal, Plants, Developmental Biology
Abstract

Model organisms are widely used in research as accessible and convenient systems to study a particular area or question in biology. Traditionally only a handful of organisms have been widely studied, but modern research tools are enabling researchers to extend the set of model organisms to include less-studied and more unusual systems. This Forum highlights a range of 'non-model model organisms' as emerging systems for tackling questions across the whole spectrum of biology (and beyond), the opportunities and challenges, and the outlook for the future.

Published
2017

27. Unraveling mechanisms of human brain evolution.

Author

Lancaster, Madeline A.

Subjects
*HUMAN evolution, *HUMAN biology, *BRAIN anatomy, *NEURAL development, *OPEN-ended questions
Abstract

Evolutionary changes in human brain structure and function have enabled our specialized cognitive abilities. How these changes have come about genetically and functionally has remained an open question. However, new methods are providing a wealth of information about the genetic, epigenetic, and transcriptomic differences that set the human brain apart. Combined with in vitro models that allow access to developing brain tissue and the cells of our closest living relatives, the puzzle pieces are now coming together to yield a much more complete picture of what is actually unique about the human brain. The challenge now will be linking these observations and making the jump from correlation to causation. However, elegant genetic manipulations are now possible and, when combined with model systems such as organoids, will uncover a mechanistic understanding of how evolutionary changes at the genetic level have led to key differences in development and function that enable human cognition. This perspective discusses the challenge of understanding what sets the human brain apart and proposes how the wealth of modern tools may allow for going from correlation to causation to understand the origins and biology behind human brain evolution. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Circadian clocks in human cerebral organoids

Author

Rzechorzek, Nina M, primary, Sutcliffe, Magdalena A, additional, Mihut, Andrei, additional, Baranes, Koby, additional, Karam, Nuzli, additional, Sánchez, Daniel Lloyd-Davies, additional, Peak-Chew, Sew Y, additional, Zeng, Aiwei, additional, Poulin, Noah, additional, Seinkmane, Estere, additional, Karim, Kaiser, additional, Proctor, Christopher M, additional, Kotter, Mark, additional, Lancaster, Madeline A, additional, and Beale, Andrew D, additional

Published
2024
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29. MEA-NAP compares microscale functional connectivity, topology, and network dynamics in organoid or monolayer neuronal cultures

Author

Sit, Timothy PH, primary, Feord, Rachael C, additional, Dunn, Alexander WE, additional, Chabros, Jeremi, additional, Oluigbo, David, additional, Smith, Hugo H, additional, Burn, Lance, additional, Chang, Elise, additional, Boschi, Alessio, additional, Yuan, Yin, additional, Gibbons, George M, additional, Khayat-Khoei, Mahsa, additional, De Angelis, Francesco, additional, Hemberg, Erik, additional, Hemberg, Martin, additional, Lancaster, Madeline A, additional, Lakatos, Andras, additional, Eglen, Stephen J, additional, Paulsen, Ole, additional, and Mierau, Susanna B, additional

Published
2024
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31. Voices of biotech research

Author

Annabi, Nasim, Baker, Matthew, Boettiger, Alistair, Chakraborty, Debojyoti, Chen, Yvonne, Corbett, Kizzmekia S., Correia, Bruno, Dahlman, James, de Oliveira, Tulio, Ertuerk, Ali, Yanik, Mehmet Fatih, Henaff, Elizabeth, Huch, Meritxell, Iliev, Iliyan D., Jacobs, Thomas, Junca, Howard, Keung, Albert, Kolodkin-Gal, Ilana, Krishnaswamy, Smita, Lancaster, Madeline, Macosko, Evan, Martínez-Núñez, Mario Alberto, Miura, Kyoko, Molloy, Jenny, Cruz, Andrés Ochoa, Platt, Randall J., Posey, Jr., Avery D., Shao, Huilin, Simunovic, Mijo, Slavov, Nikolai, Takebe, Takanori, Vandenberghe, Luk H., Varshney, Rajeev K., and Wang, Jianbin

Published
2021
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34. ISSCR standards for the use of human stem cells in basic research

Author

Ludwig, Tenneille E., Andrews, Peter W., Barbaric, Ivana, Benvenisty, Nissim, Bhattacharyya, Anita, Crook, Jeremy M., Daheron, Laurence M., Draper, Jonathan S., Healy, Lyn E., Huch, Meritxell, Inamdar, Maneesha S., Jensen, Kim B., Kurtz, Andreas, Lancaster, Madeline A., Liberali, Prisca, Lutolf, Matthias P, Mummery, Christine L., Pera, Martin F., Sato, Yoji, Shimasaki, Noriko, Smith, Austin G., Song, Jihwan, Spits, Claudia, Stacey, Glyn, Wells, Christine A., Zhao, Tongbiao, Mosher, Jack T., Ludwig, Tenneille E., Andrews, Peter W., Barbaric, Ivana, Benvenisty, Nissim, Bhattacharyya, Anita, Crook, Jeremy M., Daheron, Laurence M., Draper, Jonathan S., Healy, Lyn E., Huch, Meritxell, Inamdar, Maneesha S., Jensen, Kim B., Kurtz, Andreas, Lancaster, Madeline A., Liberali, Prisca, Lutolf, Matthias P, Mummery, Christine L., Pera, Martin F., Sato, Yoji, Shimasaki, Noriko, Smith, Austin G., Song, Jihwan, Spits, Claudia, Stacey, Glyn, Wells, Christine A., Zhao, Tongbiao, and Mosher, Jack T.

Abstract

The laboratory culture of human stem cells seeks to capture a cellular state as an in vitro surrogate of a biological system. For the results and outputs from this research to be accurate, meaning-ful, and durable, standards that ensure reproducibility and reli-ability of the data should be applied. Although such standards have been previously proposed for repositories and distribution centers, no widely accepted best practices exist for laboratory research with human pluripotent and tissue stem cells. To fill that void, the International Society for Stem Cell Research has developed a set of recommendations, including reporting criteria, for scientists in basic research laboratories. These criteria are de-signed to be technically and financially feasible and, when imple-mented, enhance the reproducibility and rigor of stem cell research.

Published
2024
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36. Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders

Author

Brennand, Kristen J, Marchetto, M Carol, Benvenisty, Nissim, Brüstle, Oliver, Ebert, Allison, Belmonte, Juan Carlos Izpisua, Kaykas, Ajamete, Lancaster, Madeline A, Livesey, Frederick J, McConnell, Michael J, McKay, Ronald D, Morrow, Eric M, Muotri, Alysson R, Panchision, David M, Rubin, Lee L, Sawa, Akira, Soldner, Frank, Song, Hongjun, Studer, Lorenz, Temple, Sally, Vaccarino, Flora M, Wu, Jun, Vanderhaeghen, Pierre, Gage, Fred H, and Jaenisch, Rudolf

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, Neurological, Brain, Brain Diseases, Drug Discovery, Humans, Induced Pluripotent Stem Cells, Mosaicism, Neurogenesis, Precision Medicine, Clinical Sciences, Biochemistry and cell biology
Abstract

As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.

Published
2015

37. Multi-omic analysis of guided and unguided forebrain organoids reveal differences in cellular composition and metabolic profiles

Author

Oehlenschlaeger, Marie S., primary, Jensen, Pia, additional, Havelund, jesper F., additional, Sutcliffe, Magdalena, additional, Elmkvist, Sofie B., additional, Criscuolo, Lucrezia, additional, Wingett, Steven W., additional, Jakobsen, Lene A., additional, Brewer, Jonathan, additional, Faergeman, Nils J, additional, Lancaster, Madeline A, additional, Larsen, Martin R, additional, and Bogetofte, Helle, additional

Published
2023
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40. AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis

Author

Louie, Carrie M, Caridi, Gianluca, Lopes, Vanda S, Brancati, Francesco, Kispert, Andreas, Lancaster, Madeline A, Schlossman, Andrew M, Otto, Edgar A, Leitges, Michael, Gröne, Hermann-Josef, Lopez, Irma, Gudiseva, Harini V, O'Toole, John F, Vallespin, Elena, Ayyagari, Radha, Ayuso, Carmen, Cremers, Frans PM, den Hollander, Anneke I, Koenekoop, Robert K, Dallapiccola, Bruno, Ghiggeri, Gian Marco, Hildebrandt, Friedhelm, Valente, Enza Maria, Williams, David S, and Gleeson, Joseph G

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Neurosciences, Eye Disease and Disorders of Vision, Neurodegenerative, Eye, Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Amino Acid Substitution, Animals, Carrier Proteins, Cell Death, Cell Line, Cytoskeletal Proteins, Humans, Italy, Mice, Opsins, Photoreceptor Cells, Vertebrate, Proto-Oncogene Proteins, Retinal Degeneration, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Degeneration of photoreceptors is a common feature of ciliopathies, owing to the importance of the specialized ciliary structure of these cells. Mutations in AHI1, which encodes a cilium-localized protein, have been shown to cause a form of Joubert syndrome that is highly penetrant for retinal degeneration. We show that Ahi1-null mice fail to form retinal outer segments and have abnormal distribution of opsin throughout their photoreceptors. Apoptotic cell death of photoreceptors occurs rapidly between 2 and 4 weeks of age in these mice and is significantly (P = 0.00175 and 0.00613) delayed by a reduced dosage of opsin. This phenotype also shows dosage-sensitive genetic interactions with Nphp1, another ciliopathy-related gene. Although it is not a primary cause of retinal blindness in humans, we show that an allele of AHI1 is associated with a more than sevenfold increase in relative risk of retinal degeneration within a cohort of individuals with the hereditary kidney disease nephronophthisis. Our data support context-specific roles for AHI1 as a contributor to retinopathy and show that AHI1 may explain a proportion of the variability in retinal phenotypes observed in nephronophthisis.

Published
2010

48. Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes

Author

Wellcome Trust, UK Research and Innovation, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Autism Research Trust, Simons Foundation Autism Research Initiative, Templeton World Charity Foundation, National Institute of Mental Health (US), Junta de Andalucía, Max Planck Society, Helmholtz Association, Canada First Research Excellence Fund, Warrier, Varun, Stauffer, Eva-María, Huang, Qin Qin, Wigdor, Emilie M., Slob, Eric A. W., Seidlitz, Jakob, Ronan, Lisa, Valk, Sofie L., Mallard, Travis T., Grotzinger, Andrew D., Romero García, Rafael, Baron-Cohen, Simon, Geschwind, Daniel H., Lancaster, Madeline A., Murray, Graham K., Gandal, Michael J., Alexander-Bloch, Aaron, Won, Hyejung, Martin, Hilary C., Bullmore, Edward T., Bethlehem, Richard A. I., Wellcome Trust, UK Research and Innovation, National Institute for Health Research (UK), Cambridge Biomedical Research Centre, Autism Research Trust, Simons Foundation Autism Research Initiative, Templeton World Charity Foundation, National Institute of Mental Health (US), Junta de Andalucía, Max Planck Society, Helmholtz Association, Canada First Research Excellence Fund, Warrier, Varun, Stauffer, Eva-María, Huang, Qin Qin, Wigdor, Emilie M., Slob, Eric A. W., Seidlitz, Jakob, Ronan, Lisa, Valk, Sofie L., Mallard, Travis T., Grotzinger, Andrew D., Romero García, Rafael, Baron-Cohen, Simon, Geschwind, Daniel H., Lancaster, Madeline A., Murray, Graham K., Gandal, Michael J., Alexander-Bloch, Aaron, Won, Hyejung, Martin, Hilary C., Bullmore, Edward T., and Bethlehem, Richard A. I.

Abstract

Our understanding of the genetics of the human cerebral cortex is limited both in terms of the diversity and the anatomical granularity of brain structural phenotypes. Here we conducted a genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging-derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,663 individuals and identified 4,349 experiment-wide significant loci. These phenotypes include cortical thickness, surface area, gray matter volume, measures of folding, neurite density and water diffusion. We identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with cortical expansion are associated with cephalic disorders. Finally, we identified complex interphenotype and inter-regional genetic relationships among the 13 phenotypes, reflecting the developmental differences among them. Together, these analyses identify distinct genetic organizational principles of the cortex and their correlates with neurodevelopment.

Published
2023

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