It Takes a "Village of Stem Cells and Progenitor Cells" to Build a Brain.

Abstract

A small pool of neural stem cells generates diverse differentiated cells that underpin a complex network of neuronal circuits and enable the brain of higher eukaryote to carry out sophisticated intellectual and cognitive tasks. Neural stem cells can generate differentiated cells directly or indirectly through producing intermediate progenitor cells (IPCs). The functional identity of IPCs must be precisely distinguished from neural stem cells, and defects in specifying their functional identity can result in the formation of aberrant neural stem cells at the expense of differentiated cells. My thesis work revealed a mechanism that regulates the competence of neural stem cells to generate IPCs and a mechanism that promotes precise specification of IPCs. These two mechanisms likely function cooperatively to ensure the proper IPCs production in the neural stem cell lineage. The brain of a fruit fly larva possesses two populations of neural stem cells (type I and type II neuroblasts) that generate progeny with distinct functional characteristics. I identified a transcription factor called buttonhead that endows type II neuroblasts with the unique competence to generate intermediate neural progenitors (INPs), which undergo limited proliferation to generate differentiated cells. Type II neuroblasts lacking buttonhead function lose the capacity to generate INPs. By contrast, mis-expressing buttonhead enables type I neuroblasts to generate INPs which never exist in wild type type I neuroblast lineages. Thus, buttonhead plays a key role in regulating the neuroblast competence to generate INPs during fly larval brain neurogenesis. Separately, I identified the klumpfuss gene that plays a key role in preserving a steady pool of neuroblasts. Type II neuroblasts lacking klumpfuss function prematurely differentiate. By contrast, mis-expressing klumpfuss in uncommitted INPs leads to the formation of supernumerary neuroblasts. Thus, rapid down-regulation of klumpfuss function in uncommitted INPs is essential for their commitment to an INP functional identity. In summary, Klumpfuss functions as a transcriptional regulator to promote neuroblast self-renewal and prevent a precocious commitment to the INP identity. Since Buttonhead and Klumpfuss are highly conserved from flies to humans, their homologs might also regulate neural stem cells during vertebrate neurogenesis.