Brain complexity is implemented by astounding diversity of cell types connected in appropriate numbers and combinations. The precise control of neural progenitor/stem cell (NPC/NSC) division and differentiation is a prerequisite for the development and maintenance of circuit integrity, plasticity and regeneration. In the laboratory, our present interest is to develop various genetic and optical tools, by which we hope to gain access to the complete development from single stem (progenitor) cells to their progeny-derived neural circuits in distinct brain regions of zebrafish (Danio rerio), and thereby elucidating the fundamental logics underlying the determination of cell number, neuronal diversity, functional property of neural circuits.
The ongoing projects:
Embryonic origin of adult retinal stem cells
Embryonic retinal progenitor cells are capable of generating all major retinal cells, as well as retinal stem cells. The unsolved questions are: Is there any embryonic progenitor subpopulation pre-specified for stem cell lineage? If not, when do the progenitors make the choice of differentiating into the neuronal lineages or becoming the stem cells? What are the extrinsic factors required for such choice? More intriguingly, what is the intrinsic change in an embryonic progenitor that endows it with the self-renewal property of a true neural cell. We attempt to adopt various advance tools, including genetic mosaic labeling, in-vivo lineage tracing, high-resolution imaging, and high-throughput genetic screening approach to tackle these questions. This line of the research can also be extended into studies of the neural stem cell niches in other brain regions, thereby rendering the possibility of probing fundamental principles underlying the generation of neural stem cells.
Timing control of neurogenesis
The development of neural tissues of the right size and cellular composition largely relies on the precise temporal control of neurogenesis, in which the switch of NSCs between the quiescent and proliferative states, as well as between the proliferative and differentiating states, are the keys. Combining in vivo imaging and single-cell genetic manipulations, we attempt to dissect the cellular rules governing such inter-state switches, as well as the underlying genetic basis. This study will provide insights into how time is encoded in neurogenesis, as well as insights into various development-related brain diseases, including brain tumors.
Functional analysis of neural circuit development
In development, a given neural tissue is generated by assembly of neural progenitor cells, each of which gives rise to a lineage of differentiated neural cells that are connected into lineage-based microcircuits. The signal processing properties of such circuits are still far from understood. At the tissue level, such lineages and their derived circuits add up to form a complete tissue. We will utilize the lineage labeling and in vivo calcium imaging approach to conduct systematic analysis of neural circuit development. We hope that this line of the study eventually provides us with the principle of the assembly of functional neural circuits.