Mary E. Hatten, Ph.D.
Frederick P. Rose Professor
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 into medulloblastoma, a prevalent childhood metastatic brain tumor.
Using the mouse cerebellar cortex as a model, Hatten studies the mechanisms of cerebellar neurogenesis and migration during central nervous system (CNS) development. Her lab pioneered the development of video imaging methods to view the dynamics of CNS neuronal migration along glial fibers. Using these methods, Hatten has revealed several key steps including the extension of a highly polarized, leading process in the direction of migration, the assembly of an interstitial adhesion junction beneath the cell soma, the formation of a perinuclear tubulin cage to maintain posterior positioning of the nucleus, and the 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, Hatten has used a method known as translating ribosome affinity purification (TRAP) to reveal dramatic changes in multiple chromatin remodeling reactomes of postmigratory neurons during the formation of cerebellar circuitry. Notably, the 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 that changes in chromatin remodeling genes in postmigratory neurons are critical for the formation of cerebellar circuitry.
The Hatten lab 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, mutations, known as copy number variants, 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, Hatten has developed protocols to differentiate induced pluripotent stem cells (iPSCs) into cerebellar neurons. To characterize iPSC-derived neurons, she uses bacTRAP technology developed in the lab of Nathaniel Heintz and an implantation assay developed in her own lab to test whether implanted human cerebellar neurons will migrate to the correct layer and incorporate into the mouse cerebellar circuitry.