The large human cerebral cortex is thought to arise from a specialized population of
outer radial glia (oRG) neural stem cells in the outer subventricular zone (OSVZ). These
stem cells divide to produce intermediate neural progenitors (INPs) that themselves
divide to produce 8-12 neurons. In contrast, most non-primate neural stem cells produce
1 or 2 neurons with each division, resulting in a smaller brain. Thus, mouse and fish
provide a relatively poor model for primate brain expansion, and direct study of primate
fetal brain tissue is problematic.
Over the past few years, our lab and others have developed a Drosophila model
for understanding oRG-like stem cell lineages. We discovered a population of Drosophila
brain neural stem cells (called type II neuroblasts; T2NBs) that generate INPs which
each generate 8-12 neurons, similar to primate oRG stem cells. Now we can use the
power and rapidity of Drosophila genetics to characterize the role of T2NBs in brain
development, and suggest testable hypotheses for human brain organoid research.
We previously discovered a series of transcription factors (TFs) and RNA-binding
proteins that are sequentially expressed in T2NBs over the five days of larval life; these
are excellent candidates for specifying the “temporal identity” of neurons in the lineage.
We also discovered a series of TTFs that were sequentially expressed in each INP as it
produced its lineage, and showed one of them (Eyeless, Ey; Pax6) was a validated
functional temporal factor that specified late-born neuron identity. But many open
questions remained: What are the neurons born from each temporal window in the T2NB
lineage? Do the candidate temporal factors in T2NBs actually specify neuronal identity?
Most TTFs are transiently expressed in progenitors (neuroblasts and INPs) but lack adult
expression; how are TTF-specified neuronal identities consolidated and maintained in
the adult fly? Are there TTF target genes that act to maintain neuronal identity? And
lastly, how is T2NB temporal identity and INP temporal identity integrated to specify
unique neuronal subtypes? These questions will be addressed in Aims 1-4, respectively.
Our findings will provide insight into the role of INPs in expanding brain size in
Drosophila, and suggest focused hypotheses to test for conserved mechanisms in
primate tissue. Furthermore, our results may shed light on the development of the
central complex, a conserved insect brain region used for celestial navigation of flies,
bees, and butterflies.