Research Interest My lab investigates how different brain cells, neurons and glia, are generated from neural stem cells and how brain cells form the neuronal network. These questions are fundamentally important to understand brain development. Knowledge of the developmental events will provide insight into the molecular and cellular mechanisms that underpin neurological diseases, such as Parkinson’s disease, autism, schizophrenia and depression. We combine several molecular and cellular approaches, including mouse genetics, in vitro assays, genomics, developmental neuroanatomy, and embryonic stem cells in our studies. Our on-going projects focus on two embryonic brain regions, the diencephalon (thalamus and habenular) and the mes-metencephalon (midbrain and cerebellum).

Molecular mechanisms of differentiation of habenular and thalamic neurons The thalamus and the associated habenula are derived from closely related progenitor domains. They together play important roles in modulating sensory, motor, cognitive and emotive functions. Habenular neurons receive inputs from the limbic system, and in turn connect and modulate the dopamine and serotonin systems of the midbrain and hindbrain. By contrast, thalamic neurons receive peripheral sensory inputs and project rostrally to the cortex. Abnormal formation and function of the habenula and thalamus have been implicated in brains disorders, such as depression, schizophrenia, sleeping disorders, and epilepsy. We recently identify key molecules that regulate the differentiation between habenular and thalamic neurons. Our long-term goal is to determine the molecular mechanisms that regulate thalamic and habenular identities and connectivities. Ultimately, this information will facilitate understanding the brain disorders resulting from abnormal formation and/or function of the thalamus and habenula.

Radial glial development in the cerebellum During cortical development of the cerebrum and cerebellum, radial glia cells in the ventricular zone provide guidance for neuronal migration and serve as stem cells for neurons and glial cells. Therefore, radial glial development is crucial for the formation of normal cortical architectonics. In contrast to the transient appearance of radial glia in the neocortex, cerebellar radial glia transform into specialized radial glia-like cells, called Bergmann glia. Bergmann glia maintain only the long basal processes and persist throughout the life of the animal. During cerebellar development, the Bergmann glial fibers provide scaffolds for migratory neurons. Interestingly, in both immature and mature cerebellum, Bergmann glia display hallmarks of neural stem cells. We recently discover the first known genetic mutation that specifically blocks Bergmann glial generation in mice. Analyses of the mutant mice also uncover a previously unappreciated function of Bergmann glia in the morphogenesis of the cerebellar cortex. Using whole genome transcriptome analysis, we identify putative genetic determinants for Bergmann glial generation. Remarkably, many of these Bergmann glia-specific genes have been implicated in the malignancy of glioma and medulloblastoma in adults and children, the most common primary malignant brain tumors in adults and children. These exciting findings will allow us to define the molecular and cellular mechanisms controlling Bergmann glial generation in the developing cerebellum. The acquired information would shed light on the molecular pathways leading to tumorigenesis in the brain.

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