Genetically, autism can broadly be segregated into syndromic and non-syndromic forms. Accounting for a small percentage of total ASD cases, syndromic ASD includes incidences of the disease with known genetic cause and unique clinical presentation, while non-syndromic ASD with unknown genetic etiology accounts for the remaining majority of ASD cases (Sztainberg and Zoghbi, 2016). The genetic underpinnings of non-syndromic ASD likely involve small effects of many genes and/or rare de novo mutations in a susceptible genetic background (de la Torre-Ubieta et al, 2016). Unfortunately, non-syndromic ASD is difficult to model precisely because of this genetic heterogeneity. The use of human-induced pluripotent stem cells (hiPSCs) offers an opportunity to uncover some of the molecular mechanisms behind non-syndromic ASD. hiPSCs possess the same genetic make-up of the individual they were derived from. Thus, hiPSCs derived from individuals with non-syndromic ASD can accurately recapitulate the heterogeneous genetics found in this form of the disease.
Recently, our laboratory and collaborators utilized hiPSCs to model non-syndromic ASD by generating hiPSC lines from eight non-syndromic ASD males (diagnosed via behavior consistent with DSM-IV criteria) along with five healthy male control individuals (Marchetto et al, 2017). Known syndromic forms of ASD were ruled out in all individuals involved with this study via exome sequencing and copy-number variant analysis. On the basis of MRI scans conducted between 2–4 years of age, all ASD individuals were found to possess mild to severe macrocephaly, defined as larger than average total brain volume compared with typically developing individuals. We hypothesized that ASD individuals sharing a co-morbidity would also share disruptions in common cellular phenotypes and signaling pathways, thereby increasing our ability to detect disruptions in these processes.
Initial observations indicated that both ASD hiPSCs and neural progenitor cells (NPCs) derived from hiPSCs proliferated at a higher rate than control cells and displayed decreased Wnt signaling. Pharmacological enhancement of the Wnt pathway rescued this proliferative phenotype. Interestingly, we have also found that disrupted Wnt signaling during mouse embryonic development leads to transient brain overgrowth and behaviors analogous to human symptoms of ASD, such as aberrant social and repetitive behaviors (Belinson et al, 2016). This remarkable pathway conservation between species suggests that aberrant Wnt signaling might have a critical role in ASD development.
In addition to NPCs, neurons were differentiated from ASD iPSC lines and displayed decreases in synapse number, which lead to defective network properties in ASD neuronal cultures. RNA sequencing was also performed in iPSCs, NPCs, and neurons, revealing both previously described and novel misregulated genes and pathways in ASD cells, including enrichment of genes linked with brain development in NPCs, likely reflecting the previously observed brain overgrowth phenotypes. A number of genes were also found to be misregulated during differentiation of NPCs to neurons in ASD cell lines, including various cation channels that might be responsible for aberrant network connectivity.
Our study illustrates that novel pathways and physiological processes in human cells can be identified in a non-syndromic neurological disorder if classified by endophenotypes. Further exploration of the genes/pathways identified in this study and the identification of new pathways associated with neurological disease in human cells promises to aid the development of more effective clinical targets.
Funding and disclosure
This work was supported by a grant from the Simons Foundation for Autism Research International (SFARI) to AW-B and a Harwell Foundation Postdoctoral Fellowship to LB. The authors declare no conflict of interest.
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Bury, L., Wynshaw-Boris, A. Modeling Non-Syndromic Autism with Human-Induced Pluripotent Stem Cells. Neuropsychopharmacol. 43, 219–220 (2018). https://doi.org/10.1038/npp.2017.195