Cellular Phenotypes in Human iPSC-Derived Neurons from a Genetic Model of Autism Spectrum Disorder
Aditi Deshpande,
Smita Yadav,
Dang Q. Dao,
Zhi-Yong Wu,
Kenton C. Hokanson,
Michelle K. Cahill,
Arun P. Wiita,
Yuh-Nung Jan,
Erik M. Ullian,
Lauren A. Weiss
Affiliations
Aditi Deshpande
Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
Smita Yadav
Howard Hughes Medical Institute , University of California, San Francisco, San Francisco, CA 94158, USA; Department of Physiology , University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics , University of California, San Francisco, San Francisco, CA 94158, USA
Dang Q. Dao
Department of Ophthalmology, University of California, San Francisco, CA 94143, USA
Zhi-Yong Wu
Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA
Kenton C. Hokanson
Department of Ophthalmology, University of California, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA
Michelle K. Cahill
Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA
Arun P. Wiita
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA
Yuh-Nung Jan
Howard Hughes Medical Institute , University of California, San Francisco, San Francisco, CA 94158, USA; Department of Physiology , University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics , University of California, San Francisco, San Francisco, CA 94158, USA
Erik M. Ullian
Department of Ophthalmology, University of California, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA
Lauren A. Weiss
Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding author
Summary: A deletion or duplication in the 16p11.2 region is associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. In addition to clinical characteristics, carriers of the 16p11.2 copy-number variant (CNV) manifest opposing neuroanatomical phenotypes—e.g., macrocephaly in deletion carriers (16pdel) and microcephaly in duplication carriers (16pdup). Using fibroblasts obtained from 16pdel and 16pdup carriers, we generated induced pluripotent stem cells (iPSCs) and differentiated them into neurons to identify causal cellular mechanisms underlying neurobiological phenotypes. Our study revealed increased soma size and dendrite length in 16pdel neurons and reduced neuronal size and dendrite length in 16pdup neurons. The functional properties of iPSC-derived neurons corroborated aspects of these contrasting morphological differences that may underlie brain size. Interestingly, both 16pdel and 16pdup neurons displayed reduced synaptic density, suggesting that distinct mechanisms may underlie brain size and neuronal connectivity at this locus. : Deshpande et al. show that neurons derived from individuals harboring neurodevelopmental disorders caused by the 16p11.2 deletion or duplication manifest contrasting cellular phenotypes that may underlie the macro- or microcephaly observed in carriers, respectively. Comparable functional changes in deletion- and duplication-derived neurons suggest similar mechanisms underlying common clinical features, like autism. Keywords: 16p11.2 CNV, neurons, iPSC, microcephaly, macrocephaly, neurodevelopmental disorders, autism, deletion, duplication
