期刊
CELL STEM CELL
卷 27, 期 1, 页码 35-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2020.06.004
关键词
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资金
- New York State Stem Cell Science Program (NYSTEM) award [C030137]
- Melanoma Research Alliance
- NYSTEM facility award [N13S-011]
- NIH Cancer Center [P30 CA008748]
- Ruth L. Kirschstein F30 M.D./Ph.D. pre-doctoral fellowship from the NIH [F30 MH113343-01A1]
- National Institute of General Medical Sciences [T32GM007739]
- NIH Director's New Innovator Award [DP2CA186572]
- NIH Mentored Clinical Scientist Research Career Development Award [K08AR055368]
- Starr Cancer Consortium
- Pershing Square Sohn Foundation
- Alan and Sandra Gerry Metastasis Research Initiative at the Memorial Sloan Kettering Cancer Center
- Harry J. Lloyd Foundation
- Ruth L. Kirschstein National Research Service Award (NRSA) predoctoral fellowship (F31) award as part of the National Cancer Institute of the National Institutes of Health [F31CA196305]
- Joanna M. Nicolay Melanoma Foundation Research Scholar Award 2014
- Robert B. Catell Fellowship
Autism is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restricted interests, and repetitive behaviors. Despite significant advances in the genetics of autism, understanding how genetic changes perturb brain development and affect clinical symptoms remains elusive. Here, we present a multiplex human pluripotent stem cell (hPSC) platform, in which 30 isogenic disease lines are pooled in a single dish and differentiated into prefrontal cortex (PFC) lineages to efficiently test early-developmental hypotheses of autism. We define subgroups of autism mutations that perturb PFC neurogenesis and are correlated to abnormal WNT/bcatenin responses. Class 1 mutations (8 of 27) inhibit while class 2 mutations (5 of 27) enhance PFC neurogenesis. Remarkably, autism patient data reveal that individuals carrying subclass-specific mutations differ clinically in their corresponding language acquisition profiles. Our study provides a framework to disentangle genetic heterogeneity associated with autism and points toward converging molecular and developmental pathways of diverse autism-associated mutations.
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