Our project capitalizes on recent procedures that allow derivation of pluripotent stem cells from fibroblasts obtainable through a small skin biopsy from living individuals. These induced pluripotent stem cells (iPSC) can differentiate into any cell types of the body, including neural stem cells (NSCs). We will use these methods to investigate neuronal differentiation in autism spectrum disorders (ASD). Our hypothesis states that increased brain size, a highly replicated biological phenotype in ASD, is attributable to altered dynamics of cell proliferation and/or differentiation intrinsic to NSCs, which, in turn, will correlate with specific changes in gene expression and the underlying changes in genomic sequence and/or epigenomic imprinting. To test this hypothesis, we have assembled a group of investigators with the range of expertise necessary for a multi-level and multi-dimensional approach to this problem.
In Specific Aim 1, we will derive iPSC lines from patients with ASD exhibiting an increase in head size and from typically developing children. These iPSC lines will be differentiated into NSCs. The NSC lines from ASD individuals will be compared to those derived from typically developing individuals with respect to their proliferation, cell death and differentiation into different neuronal subtypes, as well as synaptic specification.
In Specific Aim 2, we will use advanced genomics and epigenomics technologies to generate high-resolution and comprehensive datasets of variation in the genomic sequence, epigenetic marks, and transcript abundance at progenitor and mature stages of neuronal cell differentiation. We will integrate multi-level genomics and gene expression datasets with findings from cell biology and clinical phenotypes.
In Specific Aim 3, we will transplant NSCs from control and patients into the ventricles of mouse embryos in order to determine their in vivo phenotype and their ability to contribute neurons to various brain regions. The potential impact of our research is to develop cell lines derived directly from patients that will recapitulate in vitro the biological steps that enable an embryonic stem cell to differentiate into multiple CNS cell types. This project will lay the foundations for beginning to correlate genomic sequence, regulation and intensity of gene expression, cellular (biological) consequences, and patient behavior, and thus understand the biological mechanisms of disease. Candidate genes and regions found in iPSC lines can be subsequently validated with statistical significance in targeted large-scale screens. The direct analysis of specific differences in gene expression and regulation that pertain to individual patients and their clinical phenotype may offer unique insights into disease pathogenesis.

Public Health Relevance

This project will develop lines of pluripotent cells (iPSC) from individuals with autism spectrum disorders and typically developing children using cells obtained through a skin biopsy. These iPSC will be differentiated into neuronal cells, allowing us to investigate for the first time differences in neural cells proliferation, differentiation and survival in patients and controls, and to correlate such differences with underlying changes in gene expression and in the genomic sequence. The analysis of gene expression and regulation in neural cells that pertain to individual patients and their clinical phenotype may offer unique insights into disease pathogenesis.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-M (01))
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Abyzov, Alexej; Tomasini, Livia; Zhou, Bo et al. (2017) One thousand somatic SNVs per skin fibroblast cell set baseline of mosaic mutational load with patterns that suggest proliferative origin. Genome Res 27:512-523
Patriarchi, Tommaso; Amabile, Sonia; Frullanti, Elisa et al. (2016) Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1(+/-) patients and in foxg1(+/-) mice. Eur J Hum Genet 24:871-80
Brennand, Kristen J; Marchetto, M Carol; Benvenisty, Nissim et al. (2015) Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. Stem Cell Reports 5:933-945
Mariani, Jessica; Coppola, Gianfilippo; Zhang, Ping et al. (2015) FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell 162:375-390
Abyzov, Alexej; Mariani, Jessica; Palejev, Dean et al. (2012) Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492:438-42
Mariani, Jessica; Simonini, Maria Vittoria; Palejev, Dean et al. (2012) Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A 109:12770-5
Stevens, Hanna E; Mariani, Jessica; Coppola, Gianfilippo et al. (2012) Neurobiology meets genomic science: the promise of human-induced pluripotent stem cells. Dev Psychopathol 24:1443-51
Vaccarino, Flora M; Stevens, Hanna E; Kocabas, Arif et al. (2011) Induced pluripotent stem cells: a new tool to confront the challenge of neuropsychiatric disorders. Neuropharmacology 60:1355-63
Vaccarino, Flora M; Urban, Alexander Eckehart; Stevens, Hanna E et al. (2011) Annual Research Review: The promise of stem cell research for neuropsychiatric disorders. J Child Psychol Psychiatry 52:504-16
Vaccarino, Flora M; Smith, Karen Müller (2009) Increased brain size in autism--what it will take to solve a mystery. Biol Psychiatry 66:313-5