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Front Cell Neurosci. 2017 Oct 13;11:321. doi: 10.3389/fncel.2017.00321. eCollection 2017.

Human iPSC-Derived Cerebellar Neurons from a Patient with Ataxia-Telangiectasia Reveal Disrupted Gene Regulatory Networks.

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Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St. Lucia, QLD, Australia.
Queensland Brain Institute, University of Queensland, St. Lucia, QLD, Australia.
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD, Australia.
Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
School of Biomedical Science, University of Queensland, St. Lucia, QLD, Australia.
Department of Integrated Systems Biology and Department of Pediatrics, School of Medicine and Health Services, George Washington University, Washington, DC, United States.
Illumina, Inc.,, San Diego, CA, United States.
UQ Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.


Ataxia-telangiectasia (A-T) is a rare genetic disorder caused by loss of function of the ataxia-telangiectasia-mutated kinase and is characterized by a predisposition to cancer, pulmonary disease, immune deficiency and progressive degeneration of the cerebellum. As animal models do not faithfully recapitulate the neurological aspects, it remains unclear whether cerebellar degeneration is a neurodevelopmental or neurodegenerative phenotype. To address the necessity for a human model, we first assessed a previously published protocol for the ability to generate cerebellar neuronal cells, finding it gave rise to a population of precursors highly enriched for markers of the early hindbrain such as EN1 and GBX2, and later more mature cerebellar markers including PTF1α, MATH1, HOXB4, ZIC3, PAX6, and TUJ1. RNA sequencing was used to classify differentiated cerebellar neurons generated from integration-free A-T and control induced pluripotent stem cells. Comparison of RNA sequencing data with datasets from the Allen Brain Atlas reveals in vitro-derived cerebellar neurons are transcriptionally similar to discrete regions of the human cerebellum, and most closely resemble the cerebellum at 22 weeks post-conception. We show that patient-derived cerebellar neurons exhibit disrupted gene regulatory networks associated with synaptic vesicle dynamics and oxidative stress, offering the first molecular insights into early cerebellar pathogenesis of ataxia-telangiectasia.


ataxia-telangiectasia; cerebellum; differentiation; stem cell; transcriptome

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