Heads of Laboratories
Mary E. Hatten, Ph.D.
Frederick P. Rose Professor
Laboratory of Developmental Neurobiology
Dr. Hatten is investigating the assembly of the complex cellular architecture of the mammalian brain during development. Exploring cell differentiation and migration, her research has broad significance for human genetic studies on brain diseases and clinical implications for conditions that are partially due to developmental abnormalities in the brain, such as autism, attention deficit disorder, and childhood epilepsy. Her work on cerebellar development has also provided insights on medulloblastoma, the most prevalent childhood metastatic brain tumor.
Using the mouse cerebellar cortex as a model for central nervous system development, Dr. Hatten studies mechanisms of cerebellar neurogenesis and migration. Recent studies on the neurogenesis of cerebellar granule neurons have identified two novel regulators: Wnt3 and Casein kinase 1 delta (Ck1δ). Wnt3 is a key inhibitor of granule cell precursor proliferation via activation of mitogen-activated protein kinases. In collaboration with Dr. Nagi Ayad, she has also shown that Ck1δ, an anaphase-promoting complex substrate, is required for granule cell progenitor proliferation. Parallel studies on medulloblastoma showed overexpression of WNT3 or inhibition of Ck1δ inhibit medulloblastoma formation. Thus, the granule cell provides a model for mechanisms that control both central nervous system (CNS) neurogenesis and medulloblastoma formation.
Glial-guided neuronal migration is a key step in cortical histogenesis, ushering postmitotic neurons to the position where they form synapses. The Hatten lab pioneered the development of video imaging methods to view the dynamics of CNS neuronal migration along glial fibers. In live imaging studies, key steps included the extension of a highly polarized, leading process in the direction of migration, assembly of an interstitial adhesion junction beneath the cell soma, formation of a perinuclear tubulin cage to maintain posterior positioning of the nucleus and localization of actomyosin contractile motors ahead of the nucleus.
Functional studies showed the conserved polarity protein complex mPar6 controls the actomyosin contractility in the leading process, which propels the neuron along the glial guide. Current studies focus on the small Rho GTPase Cdc42, an upstream regulator of mPar6, and the polarized trafficking of neuron-glial adhesion receptors during migration.
Dr. Hatten has also extensively studied the neuron-glial adhesion protein astrotactin (ASTN1), a receptor she discovered in 1987. The Astn1 gene is expressed by neurons migrating along glial fibers in both the cerebellum and the cerebral cortex, and genetic studies provide evidence that Astn1 functions in neuronal migration. The lab has also characterized a second member of the Astn family, Astn2, which was recently identified as a risk factor in autism, attention deficit hyperactivity disorder and other neurodevelopmental disorders. Recent experiments show Astn2 is abundant in cerebellar granule neurons during glial-guided migration and in cerebellar Purkinje neurons in the adult. ASTN2 is also expressed in the adult hippocampus and cerebral cortex. Whereas ASTN2 regulates the trafficking of ASTN1 during neuronal migration early in development, in the adult brain it also regulates the trafficking of synaptic proteins. Current studies focus on the role of ASTN2 in synaptic plasticity.
To study neurons with ASTN2 lesions from autism patients, she develops protocols to differentiate induced pluripotent stem cells (iPSCs) into cerebellar neurons. These methods derive, in part, from studies on mouse embryonic stem (mES) cells showing that mES-derived granule cells would integrate into the developing mouse cerebellum, extend axons, migrate to the correct layer and form synaptic connections with afferent mossy fibers. To further characterize iPSC-derived neurons, she uses bacTRAP technology developed by the Heintz lab.
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. She also received the Pew Neuroscience Award in 1988 and the Irma T. Hirschl Fund Career Scientist Award in 1980. Dr. Hatten is a fellow of the American Association for the Advancement of Science.
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