｜ Welcome ｜ Access-Contact ｜ C.V. ｜ Publications ｜ Japanese ｜
|Molecular and Developmental neuroscience|
|We are interested in the molecular mechanisms underlying brain development and diseases. How such complex, fine and beautiful structures are formed from single fertilized eggs? Especially, we are focusing on the following points.|
|Brain of higher mammals
We are interested in the brain of higher mammals. Although mice are commonly used to investigate the molecular mechanisms underlying the formation and diseases of the brain, mice do not have several important structures that higher mammals have. We are therefore using the brain of carnivore ferrets, which have been commonly used for anatomical and physiological experiments. Ferrets have well-developed brain structures such as the gyrencephalic brain, ocular dominance columns in the visual cortex, and the magnocellular/parvocellular pathways in the visual system.
In the late Larry Katz's lab at Duke/HHMI, we fabricated a custom-made ferret microarray and found several molecules with intriguing expression patterns (Journal of Neuroscience 2004). We uncovered that FoxP2 is selectively expressed parvocellular neurons in the ferret and monkey LGN (Cerebral Cortex 2013). Using these molecules, we examined the mechanisms underlying visual system development (Neuroscience 2009, PLoS One 2010).
To investigate molecular mechanisms in ferrets, we recently established a method to manipulate gene expressions using in utero electroporation (Molecular Brain 2012). This is the first application of in utero electroporation to higher mammals, and is useful to express transgenes into the OSVZ (Biology Open 2013). By combining in utero electroporation and the CRISPR/Cas9 system, we established gene knockout methods in the ferret cerebral cortex (Cell Reports 2017). Using our methods, we have uncovered the molecular mechanisms of cortical folding (i.e. gyrification). We found that FGF signaling, Tbr2 transcription factor, upper layer neurons are crucial for cortical folding (Cell Reports 2017, eLife 2017, Scientific Reports 2015, 2016). Furthermore, we made a ferret model of polymicrogyria and analysed its pathophysiology (Scientific Reports 2015, Human Molecular Genetics 2017, 2018).
Our techniques using ferrets could help our mechanistic understanding of brain development and diseases in higher mammals
Sensory systems using mice
We are also working on the mechanisms of brain development using mice.
It seems reasonable to say that the most drastic environmental changes in our entire life is birth from mothers. Before birth, embryos are protected in mothers' body, and receive oxygen and nutrients automatically. In contrast, immediately after birth, newborn babies receive environmental sensory inputs from the outside and have to start to use their brains to survive. Nevertheless, the roles of birth in brain development are not well understood. Recently, we found that the birth is the trigger to make neuronal circuits in the somatosensory and visual systems via serotonin signaling (Developmental Cell 2013). Further, we also found that behavioral maturation is also regulated by birth (Molecular Brain 2014).
Using the somatosensory cortex, we uncovered novel axonal trajectories of layer 2/3 neurons in the mouse barrel cortex, and named this trajectories "barrel nets" (Journal of Neuroscience 2010, Neuroscience 2012). Using barrel nets, we found that the cell adhesion molecule cadherin is crucial for making local neuronal circuits in the cerebral cortex (Cerebral Cortex 2015)
Other previous achievements
- In vitro differentiation of ES cells into dopaminergic neurons (Neuron 2000).
- In vitro differentiation of ES cells into retinal pigmented epithelium (PNAS 2002).
- Differentiation of ES cells into various types of neurons (Nature Neuroscience 2005, PNAS 2003, 2006).
- Involvement of MAP kinase in cerebellar long term depression (Journal of Biological Chemistry 1999).
- Involvement of p38 MAP kinase in glutamate-induced apoptosis (Journal of Biological Chemistry 1997).
- Immunostaining protocol for DiI-labeled sections (Journal of Neuroscience Methods 2008).
- Immunostaining protocol for lipophilic antigens (Journal of Neuroscience Methods 2009).
- The Thy1S promoter useful for sparse neuronal labeling (Cell Reports 2015, eNeuro 2015, Mol. and Cell. Neurosci. 2011).