We are keen to determine the cellular complexity of the brain, to elucidate how numerous distinct neurons can derive from a limited number of progenitors, and to possibly reengineer the brain for understanding its structure, function and evolution.
Genetic underpinnings of fly brain development and evolution
We use Drosophila as a genetic model system for studying the development of a complex brain. The fly cerebrum has numerous distinct neurons arising from a limited number of neural progenitors. We aim to describe each cellular lineage from the progenitor neuroblast (NB) to the individual mature neurons. We will further determine the gene regulatory networks that underlie the development of various neuronal lineages. Uncovering the lineages’ similarities and differences at both cellular and molecular levels should reveal the genetic principles of fly brain development and evolution.
A “complete” cellular developmental map of adult Drosophila brain:
The adult Drosophila cerebrum develops from about 100 pairs of NBs, each of which makes a characteristic lineage, a set of diverse neurons that form a NB clone. By stochastic clonal labeling, we have mapped the 100 or so NB clones in the adult Drosophila brain (Yu, Awasaki et al., 2013). To complete cell lineage analysis for the entire Drosophila cerebrum, we are using twin-spot MARCM (Yu et al., 2009) to map the individual neurons serially made by each of the 100 or so NBs (Yu et al., 2010, Lin et al., 2012, Wang et al., 2014). Based on molecular readouts characteristic of specific neuron classes, we will identify neurons sharing common functional properties. We will determine the relatedness of diverse neurons with respect to lineage, morphology, and function. This data will lay the foundation for elucidating the mechanisms guiding the derivation of numerous distinct yet related neuron types.
Genetic molecular mechanisms of neuronal diversification:
Following cellular characterization, we will reveal the gene regulatory networks underlying the development of diverse neuronal lineages from distinct NBs. We have made technical innovations to enable live tracking and RNA sequencing of lineage-specific NBs (Awasaki et al., 2014). Using these techniques, we are identifying genes that are differentially expressed in distinct NBs and genes that are dynamically expressed in a given NB through its extended neurogenic life. By RNA sequencing of related neuron types, we will further identify the terminal selector genes defining specific neural properties. We ultimately seek to resolve the dynamic gene regulatory networks that act in precursor cells to specify distinct neuron types based on developmental origins.
Developmental plasticity and evolution of fly brains:
We also hope to address the developmental plasticity of the brain and the genetic bases of brain polymorphisms, the substrates for brain evolution. We have shown that different NB lineages respond differently to the same perturbations in organism development (Lin et al., 2013). We plan to establish further sophisticated genetic tools for detecting brain polymorphisms and elucidating their genetic bases. Using Golic+, an enhanced gene targeting system (Chen et al., 2015), we can edit the fly genome to test the genetic principles we’ve uncovered that govern neuronal specification, developmental plasticity, and/or evolution. By reprogramming NB lineages, one can potentially build different fly brains with novel neural networks and functions.
Each NB has its own footprint in the adult brain (for detail, please see Yu & Awasaki et al., 2013).
Twin-spot MARCM permits high-resolution cell lineage analysis (for detail, please see Yu et al., 2009).
Complete neuron type sequence of the ALad lineage (for detail, please see Yu et al., 2010).
The chinmo mutant prospective DL5 PN was partially transformed into the DM3 PN (for detail, please see Kao et al., 2012).
An enhanced gene targeting system for Drosophila (for detail, please see Chen et al., 2015).