My laboratory is interested in development of the central nervous system (CNS), with an emphasis on the cellular and molecular mechanisms underlying formation of the mammalian cerebellum. The cerebellum controls motor coordination and motor learning. Recent studies in humans have also implicated the cerebellum in cognitive function. Although the cerebellum constitutes only 10% of the brain volume, it contains more than half of its total number of neurons. In contrast to the vast number of cells, there are only five different types of neurons in the cerebellum and they are arranged in three well-defined layers. Thus, the cerebellum provides an ideal system to study mechanisms controlling cell proliferation, differentiation and migration during CNS development.

Part of our research focuses on the generation of cerebellar progenitors in early embryonic periods. Previous studies have demonstrated that early development of the cerebellum and the midbrain is controlled by a signaling center at the junction of these two brain structures. This signaling center is called the mid-hindbrain organizer, because when it is transplanted to other regions of the brain in chick embryos it can induce the host tissue to form an ectopic midbrain or cerebellum. Fibroblast growth factor 8 (Fgf8), which is expressed in the mid-hindbrain junction, can mimic the mid-hindbrain organizer activity. The Fgf8 gene produces multiple Fgf8 isoforms by alternative RNA splicing, and these isoforms apparently have distinct functions. The ongoing study is to investigate how different Fgf8 isoforms orchestrate the inductive activity of the mid/hindbrain organizer.

Another area of our research relates to the differentiation of distinct cerebellar neurons. During development of the CNS, distinct neurons differentiate from a pool of seemingly homogeneous precursors. As the differentiation of neuronal precursor proceeds, their developmental potential becomes progressively restricted, and they undergo changes in gene expression which ultimately lead to distinct neuronal phenotypes. A long-standing quest of developmental neurobiology has been to understand the mechanisms underlying cell fate specification during CNS development. By combining genetic analysis, using gene targeting in embryonic stem cells and BAC transgenic technologies, together with fate mapping and gene expression profile analysis, we attempt to define the cellular and molecular events leading to the specification of distinct cerebellar neurons.