The Cerebellum in Neurodevelopmental Disease
Event Details
- Type
- Monday Lecture Series
- Speaker(s)
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Mary E. Hatten, Ph.D., Frederick P. Rose Professor and head, Laboratory of Developmental Neurobiology, The Rockefeller University
- Speaker bio(s)
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In early phases of mammalian brain development glial-guided neuronal migration establishes the laminar organization of cortical brain regions. The Astrotactin gene family provides a neuron-glial ligand for glial migration with ASTN1 serving as an adhesion protein and ASTN2 regulating the turnover of ASTN1 and trafficking of synaptic proteins. Recent studies on human patients ASTN variants show severe neuro-developmental disorders (NDDs) in both cerebellum, cortex and hippocampus with migration deficits. A loss of Astn2 in the mouse results in a range of behavioral deficits that mimic those seen in patients with ASDs, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Recently, we developed robust protocols to differentiate the principal human cerebellar neuron, Purkinje cells (PCs) from patient-derived human induced pluripotent stem cells (iPSCs). To model cerebellar circuits, we engineered a microfluidic system to culture purified human PCs with their target cells, granule cells in laminae that mimic the architectural layers of cerebellar cortex. Importantly, this system promotes circuit formation and facilitates both physiological and molecular assays of cerebellar neurons. We have used this system to identify cellular, molecular and physiological deficits in iPSC-derived PCs generated from patients with Ataxia Telangiectasia (A-T), an autosomal recessive disorder caused by mutations in the ataxia-telangiectasia mutated (ATM) gene that is characterized by progressive cerebellar neurodegeneration, chiefly affecting Purkinje cells. We further demonstrated that A-T patient iPSC-PCs have molecular and physiological deficits and that isogenic control A-T iPSC-PCs treated with small molecule inhibitors of ATM mimic the A-T disease process. Thus, the microfluidic system is a powerful model to define molecular and physiological pathways involved in cerebellar disease.
Dr. Hatten received a bachelor's degree in chemistry from Hollins College in 1971. She received her Ph.D. in biochemical sciences from Princeton University in 1975 and did her postdoctoral research in neuroscience at Harvard Medical School. She was on the New York University School of Medicine faculty from 1978 to 1987 and then at the College of Physicians and Surgeons at Columbia University. She came to Rockefeller in 1992 and was named the Frederick P. Rose Professor in 2000. In 2005, Dr. Hatten was Wiersma Visiting Professor of Neuroscience at the California Institute of Technology.
Dr. Hatten received the Weil Award from the American Association of Neuropathologists in 1996. In 1991 she received the McKnight Endowment Fund for Neuroscience Investigator Award, the Javits Neuroscience Investigator Award and a Faculty Award for Women Scientists and Engineers from the National Science Foundation. In 2015, she was awarded the Cowan-Cajal award for outstanding work in developmental neuroscience and in 2017 she was awarded the Ralph W. Gerard Prize in Neuroscience of the Society for Neuroscience She was elected to the National Academy of Sciences, USA in 2017, the National Academy of Medicine, USA in 2021 and the American Academy of Arts and Sciences in 2023.
- Open to
- Campus Only