Our laboratory is broadly interested in understanding the molecular pathways that direct the formation of the brain, and how these pathways are dysfunctional in neurodevelopmental pathologies.  We use genetic information derived from patients to guide our experiments, and combine genetic, biochemical, cell biological, and proteomic approaches to test our hypotheses in cellular and mouse models.  The long-term goal of our work is to bridge genetic information with new mechanistic knowledge of brain development to provide therapeutic strategies for the treatment of neurodevelopmental disorders. 

There are currently two areas of focus in the laboratory:

Understanding the impact of UBE3A misregulation in autism

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Changes in the activity of the ubiquitin ligase UBE3A are linked to numerous neuropsychiatric disorders.  Loss of UBE3A activity causes the severe mental retardation disorder Angelman syndrome, whereas excessive UBE3A activity, through duplication of the UBE3A gene, is linked to a highly penetrant form of syndromic autism.  These observations have long implied that UBE3A activity is carefully regulated in brain development.  In previous work, we discovered that phosphorylation of UBE3A at threonine 485 (T485) by PKA is a master regulatory switch that controls its ubiquitin ligase activity (Yi et al. Cell, 2015).  T485 is mutated in autism (T485A), further demonstrating that excessive UBE3A activity causes autistic phenotypes in children.  We are now extending these observations to an in vivo model to understand how UBE3A mutation affects brain development in mice.  Using a combination of histology, proteomics, and genetics, we are studying the brain regions and pathways that are susceptible to UBE3A dysfunction.

 

Engineering novel molecular tools for the study of neuronal development

Plants have evolved numerous biochemical pathways to respond to and utilize light.  One of these light-sensitive protein domains is the Light-Oxygen-Voltage (LOV) domain.  The LOV domain is composed of a globular fold that binds a light-responsive flavin mononucleotide, and a long, C-terminal alpha helix that unwinds when this domain is exposed to light.  This structural dark/light cycle is reversible, and in previous work, we leveraged this conformational change to cage kinase inhibitory peptides into the LOV domain (Yi et al., ACS Synthetic Biology, 2014).  This provided a method to expose the inhibitory peptide only in the presence of light, thereby providing a highly precise, non-invasive method of perturbing signaling in living cells.  We are continuing our study of this fascinating domain, and looking for new ways to utilize its unique properties to engineer new light-controllable tools.   

 

Work in our lab is generously supported by:

 

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