My laboratory is interested in transcriptional regulation of the central nervous system, trying to understand the genetic and epigenetic signaling pathways that shape cellular and behavioral brain functions. Because many of the enzymes, receptors, and signaling molecules that mediate these processes are subject to pharmacologic interventions, our long-term goal is to use the information gleaned from these studies to devise treatments for neurodegenerative or psychological brain diseases in humans, such as Alzheimerís diseases, Parkinsonís disease, mental retardation and emotional deficits. In general, our research focuses on the following two areas.

1. Transcriptional regulation of neural stem cells.

Neural stem cells have the ability to self-renew and to differentiate into all neural cell types including neurons, astrocytes and oligodendrocytes. The recent establishment of neural stem cells in the adult brain generates hope for brain repair or regenerative treatments. Understanding the molecular and cellular mechanisms governing neural stem cell maintenance, proliferation and differentiation will be key to devising strategies for molecular, cellular and pharmacological therapies for stroke, trauma and degenerative diseases either through the regulation of endogenous neural stem cells or by directing embryonic stem cells or other post-natal cell types into neural stem cells and neural lineages. Through gene expression regulation, transcription factors are known to be essential during development and in adult. Their importance is further illustrated by recent achievement of reprogramming somatic cells into pluripotent stem cells via using just a few transcription factors.

Our research will focus on members of nuclear hormonal receptor superfamily, most of which are ligand-regulated transcription factors working with a cohort of cofactors. We have previously demonstrated that TLX, an orphan nuclear receptor, is essential for maintaining neural stem cells in adult brain and that TLX-dependent stem cells facilitate spatial learning and memory (Nature, 2008). Furthermore, we also discovered that TLX plays a major role in coordinating proliferation and differentiation programs in retinal progenitor cells and that it prevents retinal degeneration and vision loss (Genes Dev., 2006). Our objectives are to tease out the nuclear receptor signaling pathways in neural stem cell maintenance, self-renewal and differentiation and to explore the function of neural stem cells in animal behavior, neural degeneration, brain aging and cancers.

2. Epigenetic regulation of CNS function.

The central nervous system has the remarkable ability to reorganize neural pathways in response to activity or experience. This neuroplasticity occurs during development, or in response to environmental stimulations including drug addiction, hormonal regulation, learning and memory, or functional compensation after brain injuries. While short-term perturbation of the brain depends upon electrical and chemical events in the nervous systems, long-term establishment or maintenance of neuroplasticity requires genetic and epigenetic interactions that lead to transcriptional modifications. Delineating the molecular pathways that regulate gene expression in neuroplasticity during development or in adulthood is not only fundamental to our knowledge on how the brain works but also critical to our understanding and treatment of neuropsychological diseases, such as mental retardation, autism, depression, and schizophrenia.

In this research area, we are focusing on Carm1 as a molecular tool to address the genetic and epigenetic circuitry involved in brain function. Carm1 is a dual function protein, acting as a coactivator for nuclear receptor signaling and as a methyltransferase that catalyzes the asymmetric dimethylation of arginines in histones and other proteins, which constitutes a part of the epigenetic histone code. Furthermore, Carm1 activity has recently been shown to be regulated by signal-dependent phosphorylation. Germline-deletion of Carm1 results in perinatal lethality due to failure of lung inflation but without observable developmental defects. Using the mouse as a model system our ongoing studies demonstrate that Carm1 is specifically expressed in post-mitotic neurons. While the CNS develops normally, conditional deletion of Carm1 in the CNS leads to severe behavioral abnormalities. Our immediate plans are to delineate the signaling pathways that regulate Carm1 activity and to investigate the Carm1-dependent epigenetic and methylation events in neurons and their impact on neuronal function and animal behaviors.