Specific Projects:

Revealing molecular control of embryonic brain asymmetry in humans Creating mouse models to study brain asymmetry The Development of cognitive asymmetry in songbirds MicroRNA functions in cortical development

Development of brain asymmetry in humans:


At first glance, the human body seems to have nearly perfect symmetry, as illustrated beautifully in DaVinci's Vitruvian Man (Fig. 1). Yet, upon closer examination, the human face is not exactly symmetric, and the heart is not located in the center of the body. Most strikingly, 90% of humans have a marked preference for using the right hand.



Because of the apparent mirror-image symmetry of the left-right hemispheres, whether human brain works symmetrically or asymmetrically has never become a question until 1865 when Doctor Paul Broca encountered a patient able to speak only one word. Broca discovered lesions on the left hemisphere of that patient's brain, which was the first evidence that language ability was asymmetrically located. Since this simple discovery, we now know that the left hemisphere is dominant for mathematics and logical analysis, while the right is more skillful at face recognition, spatial reasoning and music (Fig. 2). In other words our left brain is more like a "thinker" and our right brain is more like an "artist". With the advent of more powerful techniques such as Magnetic Resonance Imaging (MRI), we know more about anatomical asymmetry of the brain that might correlate with functional asymmetry. For instance the Sylvian fissure that separates the frontal and temporal lobes has greater slope in the right hemisphere. The planum temporale, located in the language center, is larger in the left than the right.



What, then, are the causes of brain anatomical and functional asymmetry? Is there genetic control of asymmetry during human brain development? We hypothesized that if a genetic program controlled human brain asymmetry at the embryonic or fetal stages, we should be able to detect the differences in gene expression levels and patterns between left-right hemispheres in developing embryos over time. We are using genetic screening approaches, such as microarrays, to identify asymmetrically expressed genes in human embryonic and fetal brains.


Creating mouse models to study brain asymmetry:

A well-studied lateralized manual behavior of many mammals is the food-reaching task, called paw preference. Paw preference has been observed and studied in dogs, cats, rats and mice. In rodents, while an individual mouse prefers to use either the left or right front paw, this preference becomes random at a population level. Can we use genetic tools to manipulate gene expression in the brain and alter lateralized behaviors such as paw preference in mice? We are developing mouse models to study brain asymmetry using genetic approaches, such as gene knockout and unilateral in utero cortical electroporation.

Brain asymmetry in songbirds:

A well known animal model in which brain asymmetry for a complex, learned behavior is strongly lateralized is the canary. Every canaries tested thus far (over 100 just in our collaborating lab) produce over 90% of their song with their left hemisphere. This excellent model system allows us to tackle the molecular mechanisms of brain asymmetry and how complex behavioral functions are lateralized. We are collaborating with the laboratory of Fernando Nottebohm at the Rockefeller University and trying to identify genes that control the lateralization of song in canaries.

MicroRNA functions in cortical development:


Accurate structure and precise function of the cortex depends on the production of cortical neurons in distinct regions and at specific developmental time points. Cortical neurons are derived from multiple progenitors that reside in distinct cortical regions. For example, projection neurons (glutamatergic neurons) are generated from progenitors in the dorsolateral wall of the cerebral cortex. There are at least three types of progenitors for projection neurons: neuroepithelial cells, radial glia and intermediate progenitors. We are interested in revealing the molecular control of cortical development that is regulated by a novel post-transcriptional mechanism: microRNAs. MicroRNAs (miRNAs) are ~22 nucleotide, endogenous, noncoding, small RNAs. The mature miRNA controls gene expression by binding to the 3'-untranslated region (3'-UTR) of its target gene and silencing protein translation. We have found that some miRNAs are either expressed in different developmental stages or in distinct cortical regions. We want to address the following questions: Are microRNAs required for normal cortical development? Do miRNAs control neural stem cell development in embryonic cortices? Do miRNAs play a role in cortical anterior-posterior patterning? This knowledge can help us to develop genetic tools and map the mutations of not only coding genes but also noncoding molecules, such as miRNAs, that can result in human neurological disorders and mental illness.