Our laboratory uses genetically modified mice and human induced pluripotent stem cells (iPSCs)/brain organoids to model neurological disorders, including neural developmental disorders (NDDs) and neurodegenerative diseases. We also investigate mesenchymal stem cells (MSCs), bone and dental growth and regeneration. We perform mechanistic studies at molecular, cellular, circuit, and behavioral levels, using a combination of molecular, cellular, live imaging, electrophysiology, optogenetic, chemogenetic, and behavioral approaches.

1. Brain growth and connectivity. We are interested in neural progenitor cell (NPC) behaviors, neuronal differentiation and morphology, synaptogenesis and circuit formation in the developing brain; how dysregulation of these processes leads to NDDs, including microcephaly, macrocephaly, intellectual disability (ID), and autism spectrum disorder (ASD). We approach these questions by focusing on rare disease genes and environmental factors such as Zika virus (ZIKV) infection, with the goal of identifying convergent disease mechanisms among diverse NDDs. We use both genetically modified mice and iPSC/brain organoids to identify conserved and human-specific disease mechanisms.

2. Dementia and ALS neurodegenerative disorders. The hexanucleotide (G4C2) repeat expansion in C9ORF72 gene intron causes the most common familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in humans (C9FTD/ALS). The pathogenesis includes loss-of-function (C9ORF72 haploinsufficiency) and gain-of-function (toxic dipeptides and RNAs). We discovered a C9ORF72/SMCR8-protein containing complex regulating autophagy-lysosomal function, identified C9ORF72/SMCR8 downregulation as disease risk factors, and found a synergistic interaction between loss- and gain-of-function in the pathogenesis of C9FTD/ALS. We continue to investigate pathogenesis and potential therapeutic targets of C9FTD/ALS and other dementia.

3. Dental and bone defects linked with neurological disorders. Many dementia/ALS patients have comorbidities of dental and bone impairments, which are largely neglected. Conversely, certain dental and craniofacial patients exhibit neurological deficits, as reflected by the cognitive dysfunctions in craniosynostosis patients. We are interested in the common mechanisms between neurological diseases and dental & bone defects, whether we can target these common mechanisms to prevent both neurological and bone diseases.