Modeling critical neurodevelopmental periods and underlying time-critical signaling networks of autism spectrum disorders in patient-derived neurons
Developmental Biology
Developmental Neurobiology
Cell Biology
Final Report Abstract
Autism Spectrum Disorder (ASD) is a highly heritable neurodevelopmental condition that is defined by social and communication deficits, as well as restrictive and repetitive behaviors. ASD harbors genetically highly complex backgrounds that perturb biological processes across multiple levels – from the molecular, to the cellular, to the behavioral. This timely concerted complexity poses a formidable challenge to both scientists and physicians, as traditional methods have thus far failed to produce a rigorous definition or clinically predictive model for such complex neurodevelopmental and neuropsychiatric disorders. My postdoctoral research focused on combining novel clinical assessment strategies for autism spectrum disorders with personalized human stem cell-based technologies. I worked on one of the first induced pluripotent stem cell (iPSC) models for idiopathic ASD, which we generated from subjects with early aberrant brain growth trajectories. For this, I have pioneered computational and genetic approaches to assess dynamic disease trajectories during patient-specific cortical neuron development as opposed to assessing singular disease states. My work demonstrated that an ASD-specific dynamically aberrant timing of gene regulatory networks has far reaching consequences for coordinating maturation of neuronal circuits. Importantly, this work demonstrated for the first time how a pathological priming of gene regulatory networks that evolves during early neural development triggers ASD-associated neurodevelopmental aberrations that disturb the maturational sequence of cortical neurons during development. My research showed that studying system dynamics can maximize our chances of capturing relevant mechanistic disease states, as well as the processes by which these states unfold. During the project I developed a new methodological framework for analyzing longitudinal transcriptomic data. I realized that an unbiased and holistic systems level approach may provide a more relevant insight into pathogenic processes than a singular focus on putatively mechanistic signalling pathways involved in a very complex neurodevelopmental disorder. Thus, during the course of my project, I started with a time-resolved transcriptomic assessment of ASD and control cortical neuron development and based my further hypothesis testing on these initial findings. This marginal deviation from the experimental order of the initial plan enabled me to broaden my experimental focus and led to an in depth study on the developmental origin of specific disease-associated phenotypic changes, which we identified in cortical neurons derived from autistic individuals with macrocephaly. My recent work on idiopathic autism and the development of new stem cell model systems and approaches received broad interest in the scientific community as well as in the general-interest media.
Publications
- (2019) Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. Nat. Neurosci. 22, 243
Schafer, S. T., Paquola, A. C. M., Stern, S., Gosselin, D., Ku, M., Pena, M., Kuret, T. J. M., Liyanage, M., Mansour, A. A., Jaeger, B. N., Marchetto, M. C., Glass, C. K., Mertens, J. & Gage, F. H.
(See online at https://doi.org/10.1038/s41593-018-0295-x)
