Research

We are interested in how RNA-binding proteins and non-coding RNAs govern normal brain development and function, and how posttranscriptional dysregulation at the steps of mRNA biogenesis, stability, and translation may lead to malfunction of neurons and glia in mental and neurological diseases. Taking a multidisciplinary strategy and a combination of molecular, cellular, genetics and pharmacological approaches, our current research focuses on the following directions:

Translation regulation in neuronal development, synaptic plasticity and brain disorders

Rapid and accurate regulation of protein synthesis in brain neurons, especially at the synapses, is a critical mechanism that governs neuronal network development, synaptic plasticity, and cognitive function.  We investigate molecular mechanisms controlling mRNA translation and homeostasis of key signaling molecules that govern normal brain function but are dysregulated in neurological and/or cognitive disorders, represented by brain derived neurotrophic factor (BDNF) and activators of the cyclin-dependent kinase 5 (CDK5).  We are currently focusing on several RNA-binding proteins and microRNAs that collaboratively control BDNF-TrkB signaling and Cdk5 signaling under physiological and pathological neuronal activity changes, including learning and memory, stroke and epilepsy

In addition, we have a long standing interest in the fragile X mental retardation protein (FMRP), a selective RNA-binding protein that controls mRNA translation whose absence leads to fragile X syndrome (FXS), the leading cause of inherited intellectual disability. We are currently investigating how FMRP collaborates with microRNAs to control neuronal translation in response to developmental and synaptic signals and how FMRP deficiency leads to abnormal synaptic plasticity.

Recent progress and working models>> 

Posttranslational abnormalities in psychiatric diseases

Both neuronal and myelin abnormalities contribute to the etiology of neuropsychiatric diseases.  We investigate posttranscriptional dysregulation of risk factors of mental illnesses in neurons and myelinating oligodendroglia, aiming to elucidate prevailing molecular pathways affected in psychiatric disorders.  Our current research focuses on the glia selective RNA-binding protein QKI, a key factor controlling CNS myelin formation via regulating mRNA stability, translation, and pre-mRNA processing.  Genetic alterations and deficiency of QKI are associated with psychiatric disorders represented by schizophrenia, which contributes to the myelin defects and long range disconnectivity. We have established molecular, cellular and animal models to investigate QKI-dependent regulatory network including numerous risk factors affected in psychiatric diseases. Genetic and pharmacological approaches are employed to manipulate the QKI pathway in order to promote myelination.

In addition, we have recently identified a novel pathway in which long non-coding RNAs and splicing factors cooperate to control splicing of critical factors that govern normal neuronal network development but affected in psychiatric disorders. Our current studies employ schizophrenia patient iPSC-derived neurons and vertebrate animal models that harbor aberrant alternative splicing of schizophrenia risk factors crucial for neuronal and synapse development.

Recent progress and working models>>