Research & Projects
Our current research has three broad areas:
- Understanding brain development
- Understanding molecular and cellular basis of behavior
- Identifying small molecules as drug leads to treat neurological diseases
Our facility houses many thousands of zebrafish, which are of different genetic backgrounds and which can be used to produce hundreds of thousands of embryos and larvae for research and screening purposes.
One fundamental question in brain development is how multi-potent neural progenitor/stem cells maintain replenishing populations while generating diverse differentiated neural cell types. Understanding brain development will lay an important foundation for elucidating etiology and pathogenesis mechanisms of neurodevelopmental disorders such as autism and schizophrenia. Dys-regulation of progenitor proliferation and differentiation is also a major contributing factor to cancer.
Neural stem cell division
The optical clarity and accessibility of embryonic and larval zebrafish brains make them an ideal system for direct in vivo imaging of neural stem cell (NSC) behavior. Through individual NSC labeling and in vivo time-lapse imaging, we find that vertebrate radial glia (RG), the principal NSCs in the brain, predominantly undergo asymmetric cell division (ACD) to generate a “high Notch” self-renewing and a “low Notch” differentiating daughter. This Notch asymmetry is established by evolutionarily conserved cortical polarity regulators (e.g., Par-3), and maintained by intra-lineage Notch signaling. Par-3 localizes the ubiquitin E3 ligase and Notch signaling regulator Mind bomb (Mib) to the apical side prior to NSC ACD. We are addressing how NSC asymmetry arises at both individual cell and population levels.
Molecular mechanisms of NSC self-renewal, differentiation, and quiescence
An important attribute of the zebrafish is its amenability to forward genetic screening. Through such screening, we identified an evolutionarily conserved gene that has been named fezf2. Its expression demarcates the ontogeny of NSCs in zebrafish. Functionally, fezf2 is required to promote neuronal differentiation in embryonic NSCs by positively regulating bHLH proneural and HD neuronal determination genes. In adult NSCs, fezf2 is required to promote quiescence by positively regulating Notch signaling activity. We are addressing:
- The molecular mechanisms through which fezf2 expression is restricted to NSCs
- Molecular programs that distinguish self-renewing, differentiating, and quiescent NSCs
The outcome of brain development is interconnected neuronal networks that produce functions critical for organism survival and well-being. In humans and other animals, individuals instinctively approach reward and avoid punishment, and such innate preferences drive robust learning. A fundamental understanding of the assembly and function of these circuits is essential for developing effective treatments to combat brain disorders such as drug and alcohol abuse.
Neural circuitry of stress and anxiety
Aversive sensory stimuli activate the brain’s stress axis and generate fear/anxiety-like behaviors. In larval zebrafish, darkness activates the hypothalamic pituitary (HP) axis, namely CRF-POMC neurons. In contrast, light suppresses HP and CRF-POMC activity. This HP axis regulates physiological cortisol level and camouflage that is sensitive to alcohol. Behaviorally, larval zebrafish approach light while avoiding dark, a behavior that is potentially fear/anxiety-associated. We are applying newly developed methods to dissect the underlying cellular and molecular basis of stress and anxiety, and other emotional and motivational behaviors.
Exploiting the high throughput screening capabilities of zebrafish, we develop mutant and transgenic zebrafish lines and use them to identify phenotype-modifying small molecules. Toward this effort, we embarked on a highly interdisciplinary approach to establish zebrafish and mammalian pluripotent stem cell models for Parkinson’s disease and to develop high-content screening technologies. We are continuing to discover novel actions of small molecules that can regulate the development, maintenance, and regeneration of dopamine neurons both in culture dishes and in vivo.