Cell Reports (Mar 2023)
High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways
- Hellen Weinschutz Mendes,
- Uma Neelakantan,
- Yunqing Liu,
- Sarah E. Fitzpatrick,
- Tianying Chen,
- Weimiao Wu,
- April Pruitt,
- David S. Jin,
- Priyanka Jamadagni,
- Marina Carlson,
- Cheryl M. Lacadie,
- Kristen D. Enriquez,
- Ningshan Li,
- Dejian Zhao,
- Sundas Ijaz,
- Catalina Sakai,
- Christina Szi,
- Brendan Rooney,
- Marcus Ghosh,
- Ijeoma Nwabudike,
- Andrea Gorodezky,
- Sumedha Chowdhury,
- Meeraal Zaheer,
- Sarah McLaughlin,
- Joseph M. Fernandez,
- Jia Wu,
- Jeffrey A. Eilbott,
- Brent Vander Wyk,
- Jason Rihel,
- Xenophon Papademetris,
- Zuoheng Wang,
- Ellen J. Hoffman
Affiliations
- Hellen Weinschutz Mendes
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Uma Neelakantan
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Yunqing Liu
- Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA
- Sarah E. Fitzpatrick
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA; MD-PhD Program, Yale School of Medicine, New Haven, CT 06510, USA
- Tianying Chen
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Weimiao Wu
- Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA
- April Pruitt
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA
- David S. Jin
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06510, USA
- Priyanka Jamadagni
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Marina Carlson
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA
- Cheryl M. Lacadie
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT 06510, USA
- Kristen D. Enriquez
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Ningshan Li
- Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA; SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
- Dejian Zhao
- Department of Genetics, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06510, USA
- Sundas Ijaz
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Catalina Sakai
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Christina Szi
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Brendan Rooney
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Marcus Ghosh
- Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK
- Ijeoma Nwabudike
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA; MD-PhD Program, Yale School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA
- Andrea Gorodezky
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Sumedha Chowdhury
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Meeraal Zaheer
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Sarah McLaughlin
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Joseph M. Fernandez
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Jia Wu
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Jeffrey A. Eilbott
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
- Brent Vander Wyk
- Department of Internal Medicine, Section of Geriatrics, Yale School of Medicine, New Haven, CT 06510, USA
- Jason Rihel
- Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK
- Xenophon Papademetris
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT 06510, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06510, USA
- Zuoheng Wang
- Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA
- Ellen J. Hoffman
- Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 3
p. 112243
Abstract
Summary: Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.
