RT Journal Article
SR Electronic
T1 Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 349415
DO 10.1101/349415
A1 Dwaipayan Adhya
A1 Vivek Swarup
A1 Roland Nagy
A1 Lucia Dutan
A1 Carole Shum
A1 Eva P. Valencia-Alarcón
A1 Kamila Maria Jozwik
A1 Maria Andreina Mendez
A1 Jamie Horder
A1 Eva Loth
A1 Paulina Nowosiad
A1 Irene Lee
A1 David Skuse
A1 Frances A. Flinter
A1 Declan Murphy
A1 Grainne McAlonan
A1 Daniel H. Geschwind
A1 Jack Price
A1 Jason Carroll
A1 Deepak P. Srivastava
A1 Simon Baron-Cohen
YR 2020
UL http://biorxiv.org/content/early/2020/04/25/349415.abstract
AB Background Autism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post-mortem brain studies using adult brains have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from autistic individuals with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism.Methods IPSCs were generated from 9 unrelated autistic individuals without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing, control, individuals. IPSCs were differentiated towards either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterise iPSCs at different stage of differentiation.Results A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to post-mortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated towards a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors, and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs.Conclusions Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.Competing Interest StatementThe authors have declared no competing interest.