Primary AppointmentAssociate Professor, Cell Biology
- BA, Biochemistry, Rice University
- PhD, Neuroscience, University of California, San Francisco
- Postdoc, Neurodevelopment, The Salk Institute
- Postdoc, Neurogenetics, Beth Israel Hospital, Boston, MA
Neural Development; Cell Division in Neural Stem Cells; Axon Outgrowth and Guidance
Your cerebral cortex mediates your conscious sensory perceptions, thoughts, and behaviors. To perform these functions, the cortex must develop the proper structure and circuitry during early life. Our lab works to help understand this process, and the disruptions that cause neurodevelopmental disorders.
In the embryo, the cortex begins as an epithelial sheet of neural stem cells. The sheet expands and balloons outward due to symmetric divisions of these polarized cells. Later, the stem cells divide asymmetrically, eventually generating billions of neurons and glia. The neurons and glia form a six-layered structure with different areas specialized for functions such as vision or hearing. Finally, neurons within each area must be "wired" to other specific brain regions through axonal connections. The genetic and cellular mechanisms that control all these events are only beginning to be understood, and comprise some of the most compelling mysteries of biology and medicine. How is the correct size of the cerebral cortex specified? What gives the human cortex abilities that are unique among animals? What are the changes in neural development that underlie brain malformations, seizures, intellectual disability, schizophrenia, or autism?
The long-term goal of our lab is to help answer these questions, and elucidate fundamental cellular mechanisms important not only in the nervous system, but in development of many tissues and disease processes. In particular, we have been using forward genetics in mice to identify novel genes involved in cortical development. We isolated several mutants with specific defects in brain growth and wiring. By identifying the mutated genes and studying the cellular roles of the encoded proteins, with both in vivo and in vitro experiments, we hope to understand how mutations in single genes can cause changes in brain structure. Our novel gene discoveries have led to studies on protein localization, the cytoskeleton, and cell shape changes within neurons, progenitor cells, and other cell types.
Axon outgrowth and guidance: how the brain is wired together
One of the mutants we isolated, called baffled, has strong defects in axon outgrowth and guidance. Axonal connections between the cortex and thalamus are delayed in their growth, especially at a critical boundary crossing. In addition, the axons are disorganized and overfasciculated (stuck together). Cortical neurons dissociated from baffled mutant brains have shorter axons in culture. By genetic mapping and cloning, we found that baffled carries a mutation in the endoplasmic reticulum (ER) chaperone protein BiP/GRP78. BiP has a well-known function in protecting aging neurons against neurodegeneration, but its roles in developing neurons had not been well studied. Our findings add to accumulating evidence suggesting that axon outgrowth and guidance are particularly vulnerable to deficits in ER functions.
Neurogenesis: how cell division mechanisms produce different daughter cells at different times to build a proper brain
The highly polarized structure of neuroepithelial stem cells places special constraints on cell division. The cell cycle, mitosis, and cytokinesis must be coordinated with nuclear migration and the proper timing of neuron production. Furthermore, the cells must split in half while maintaining their polarity and attachments within the epithelial sheet. We are studying the mechanisms of these unusual cell divisions, how the mechanisms differ between symmetric and asymmetric division, and how they may influence fates and differentiation of the daughter cells. By elucidating mechanisms of cell division in neural epithelium, we can help to understand how other epithelial tissues grow, how they may repair themselves after damage, or how errors in division lead to tumor formation.
The magoo mutant mouse has a small brain (microcephaly) due to a mutation in a kinesin motor protein, Kif20b. Kinesins can organize and move along microtubules to mediate cell shape changes and transport cargo around the cell. Kif20b is overexpressed in some cancers, but its precise cellular roles are not well understood. We showed that loss of Kif20b causes increased apoptosis of neural stem cells in the cerebral cortex, probably due to abnormalities in the shape and positioning of cytokinetic midbodies, which are required to mediate the final severing event of cell division, abscission. We hypothesize that Kif20b and its cargo/partners are important for maturation or stabilization of the midbody leading to abscission. Ongoing work includes exploring the molecular role of this kinesin and studying what goes wrong in neural stem cells, newborn neurons, and brain architecture when cytokinesis mechanisms are disrupted. Thus this small-brained mutant will help elucidate how the brain is built, and the causes of human brain malformations.