Heads of Laboratories
Frederick P. Rose Professor
Laboratory of Developmental Neurobiology
Dr. Hatten studies the development of the complex cellular architecture of the mammalian brain. Her research on how neurons differentiate and migrate has implications for the genetics of brain disease, as well as conditions that are partially due to developmental abnormalities, such as autism, attention deficit disorder, and childhood epilepsy. Her work has also provided insights on medulloblastoma, a prevalent childhood metastatic brain tumor.
Using the mouse cerebellar cortex as a model for central nervous system (CNS) development, Dr. Hatten studies mechanisms of cerebellar neurogenesis and migration. The Hatten lab pioneered the development of video imaging methods to view the dynamics of CNS neuronal migration along glial fibers. Key steps revealed this way include 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 in her lab have shown that the conserved polarity protein complex mPar6 controls the actomyosin contractility in the leading process, propelling the neuron along the glial guide. Current studies focus on the small Rho GTPase Cdc42, an upstream regulator of mPar6, and on the polarized trafficking of neuron-glial adhesion receptors during migration.
To analyze global changes in gene expression in postmigratory neurons, Dr. Hatten uses a method known as translating ribosome affinity purification (TRAP). These studies have revealed dramatic changes in multiple chromatin remodeling reactomes of postmigratory neurons during the formation of cerebellar circuitry. Notably, Tet genes and a DNA demethylation product, 5-hydroxymethylcytosine (5hmC), are up-regulated. Genome-wide analysis of 5hmC distribution revealed the highest levels at exon start sites of most highly expressed genes. The activation of Tet enzymes elevated 5hmC levels in axon guidance and ion channel genes and knockdown of Tet1 and Tet3 by RNA interference markedly inhibited dendritic arborization of developing granule cells. Thus, her work has shown changes in chromatin remodeling genes in postmigratory neurons are critical for the formation of cerebellar circuitry.
Dr. Hatten has 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 Astn1 functions in neuronal migration. The lab has also characterized Astn2, which has been identified as a risk factor in autism, attention deficit hyperactivity disorder and other neurodevelopmental disorders. Recent experiments show that ASTN2 localizes to synapses, binds to the synaptic protein neuroligin, and functions in synaptic protein trafficking. Thus, CNVs in ASTN2 may affect synaptic output due to trafficking defects.
To study neurons with Astn2 and Tsc1 lesions from autism patients, as well as other neurogenetic defects that affect cerebellar development, she has developed protocols to differentiate induced pluripotent stem cells (iPSCs) into cerebellar neurons. To characterize iPSC-derived neurons, she uses bacTRAP technology developed by the Heintz lab and an implantation assay developed in her lab to test whether implanted human cerebellar neurons will migrate to the correct layer and incorporate into the mouse cerebellar circuitry.
A.B. in chemistry, 1971
Ph.D. in biochemical sciences, 1975
Harvard Medical School, 1975–1978
Assistant Professor, 1978–1982
Associate Professor, 1982–1986
New York University School of Medicine
Associate Professor, 1986–1988
Columbia University College of Physicians and Surgeons
The Rockefeller University
Irma T. Hirschl/Monique Weill-Caulier Trust Research Award, 1980
Pew Neuroscience Award, 1988
McKnight Endowment Fund for Neuroscience Investigator Award, 1991
National Institutes of Health Javits Neuroscience Investigator Award, 1991
Faculty Award for Women Scientists and Engineers, National Science Foundation, 1991
Weil Award, American Association of Neuropathologists, 1996
Fellow, American Association for the Advancement of Science
Penas, C. et al. Casein kinase 1δ is an APC/CCdh1 substrate that regulates cerebellar granule cell neurogenesis. Cell Rep 11, 249–260 (2015).
Govek, E.E. et al. The role of Rho GTPase proteins in CNS neuronal migration. Dev. Neurobiol. 71, 528–553 (2011).
Wilson, P.M. et al. Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. J. Neurosci. 30, 8529–8540 (2010).
Solecki, D.J. et al. Myosin II motors and F-actin dynamics drive the coordinated movement of the centrosome and soma during CNS glial-guided neuronal migration. Neuron 63, 63–80 (2009).
Salero, E. and Hatten, M.E. Differentiation of ES cells into cerebellar neurons. Proc. Natl. Acad. Sci. U.S.A. 104, 2997–3002 (2007).