During development, neuronal cell-types with phenomenal diversity are generated to assemble the functional neuro-circuits with remarkable precision. Unraveling these developmental processes is one of the main challenges in neuroscience today. Particularly, discovery of the gene regulatory networks responsible for neuronal cell-type specification is a fundamental step toward not only understanding the CNS development but also developing better treatment strategies for neurodevelopmental disorders and methods to generate specific neurons in regenerative medicine.
Our long-term goals are to dissect gene regulatory events that lead to the cellular diversity and eventually formation of functional neuro-circuits in the CNS and to understand genetic and mechanistic basis for neurodevelopmental defects, ultimately contributing to the generation of better treatment strategies for human developmental disorders. The studies in my laboratory focus on understanding the role of transcription factors, chromatin modifiers, miRNAs and extrinsic signals in CNS development. The developing spinal cord and forebrain have served as an important model system for our study, because the anatomy, cell types and extrinsic cues that influence development are relatively well characterized in the embryonic/fetal spinal cord and forebrain, providing rigorous model systems for our studies, and because developmental defects in the spinal cord and forebrain have been known to cause various human disorders.
We are utilizing unique approaches that combine mouse genetics and chick embryology to take advantage of their complementary strengths as experimental systems. We have developed several mouse models that recapitulate human conditions resulted from impaired function of gene expression regulators regulators. In addition to these animal models, we utilize embryonic stem cells as a model for cell-fate specification due to its amenability to genetic manipulations and resemblance to in vivo embryonic developmental processes. Furthermore, to gain mechanistic insights into the developmental changes in embryos and stem cells, we are taking diverse molecular and biochemical approaches. For example, we are implementing state-of-the-art tools such as chip-seq (chromatin immunoprecipitation followed by massive parallel sequencing), RNA-seq, and RISC-trap-seq.
Currently, we have three active research areas, as summarized below.
A. Gene regulatory network that directs the development of spinal cord: The role of transcription factors, such as LIM homeodomain (HD) and basic helix-loop-helix (bHLH) proteins, has been a focus of the study of neural cell-type specification over the past decades. Dissection of the gene networks in CNS development requires understanding of multidimensional inputs into the gene regulation, including transcription factors, extrinsic signals, epigenetic regulators and miRNAs. Our study aims to tackle this critical issue by specifically focusing on the gene networks for specification of motor neurons, interneurons and oligodendrocytes in the spinal cord where the developmental transcription codes are relatively well understood.
B. Understanding the function of FoxG1 and the etiology of FoxG1 syndrome in the developing brain: FoxG1 syndrome is a severe neurodevelopmental disorder, which is characterized by microcephaly, agenesis of corpus callosum, enlargement of the lateral ventricle, seizures, intellectual disability, sleep disturbances, irritability, and hand stereotypies. As FoxG1 syndrome patients exhibit great degree of social impairment, FOXG1 syndrome is classified as an autism spectrum disorder. FoxG1 syndrome is caused by de novo mutation that inactivates the FoxG1 gene, which belongs to the forkhead box transcription factor family. At an early stage of embryonic brain, FoxG1 is highly expressed in neural progenitors in the ventricular zone of the forebrain and plays important roles in keeping cells in a proliferative state and inhibiting neuronal differentiation. FoxG1 is downregulated as neural progenitors undergo differentiation and migration, and then it is strongly upregulated in the cortical plate at a later stage. While genetics studies of FoxG1 have revealed the essential functions of FoxG1 in controlling the forebrain development, the mechanisms that mediate critical actions of FoxG1 in the forebrain development remains poorly studied. We wish to dissect the basic biology of FoxG1 function that directs development of the forebrain as well as disease-causing mechanisms of FoxG1 mutations found in FoxG1 syndrome patients using an ensemble of molecular, cellular, biochemical, and genetic approaches.
C. Understanding the role of UTX/MLL4 chromatin remodeling complex in the developing brain: Chromatin remodeling complexes control the overall organization of chromatin and thereby play important roles in regulation of gene transcription. Our lab purified the first mammalian transcriptional coactivator complex that methylates histone H3-lysine 4 (H3K4). This complex possesses two crucial enzymes that modify chromatin architecture; MLL4, which methylate histone H3 lysine 4 (K4), and UTX that demethylate histone H3 lysine 27 (K27). Interestingly, mutations in either MLL4 or UTX in human lead to Kabuki syndrome, a developmental disorder associated with intellectual disability and autistic symptoms. We found that MLL4 and UTX are highly expressed in the developing forebrain. We are currently investigating the roles of MLL4 and UTX in the developing cortex and how the dysregulation of MLL4 and UTX activity affects the proliferation and differentiation of neural stem cells and contributes to symptoms of Kabuki syndrome.