Our lab seeks to understand the mechanisms that underlie the generation of neural diversity in the brain. How are the thousands of different cell types produced in such an organized manner to allow proper brain function? We are using the Drosophila and mouse models to address these questions.
Drosophila embryonic neuroblasts
Fly embryo neural stem cells, called neuroblasts (NBs) are born from the neuroepithelia. In the ventral nerve cord, there are ~30 NBs per hemisegment. Each NB generates a unique lineage of neurons and glia in a stereotyped birth order. NBs go through multiple rounds of asymmetric cell division that generates a NB (self-renewal) and a differentiating daughter cell called, ganglion mother cell (GMC). The GMC divides again to produce two postmitotic progeny. Images modified from Nat Rev Neurosci, 2013.
Regulation of neuroblast competence
As they divide, NBs sequentially express the temporal identity factors, Hunchback (Hb), Kruppel (Kr), Pdm, and Castor (Cas). These transcription factors specify the identity of the progeny cells based on their birth order, and consequently, the progeny maintain the temporal identity factor's expression. For example, Hb, the first of the series, specifies all cell born early in the lineage (early-born identity). The particular identity of each early-born cell is specific to its lineage, but all early-born neural cells are specified by Hb and maintain hb transcription, a molecular marker of the timing of its birth.
NB7-1 is one of ~30NB of the embryonic ventral nerve cord. During its first 5 divisions, it makes 5 different types of motoneurons, U1-U5. Hb specifies the early-born neurons, U1 and U2, Though Hb turns off at the second division, NB7-1 is competent to produce U1/U2 neurons for another 3 divisions. Thus, the first 5 divisions of NB7-1 constitute its "early competence window." For review, see Nat Rev Neurosci, 2013.
Overexpression of Hb in late-stage NB does not result in ectopic production of early-born cells types; thus, fate specification and competence are two, independently-regulated temporal programs.
We discovered that the hb genomic locus (cyan) becomes repositioned from the interior of the NB nucleus to the periphery (nuclear lamin marked in magenta) as the NB ages over time. In NB7-1, this relocation occurs not at the end of hb transcription (division 2), but rather, at the end of the early competence window (div 5). Distal antenna (Dan, dark blue) is a nuclear factor that is transiently expressed in the NBs, and its downregulation is required to allow hb gene repositioning and the closure of the early competence window. Images modified from Kohwi et al., Cell, 2013.
Questions we are interested in addressing:
What are the mechanisms by which neuroblast competence transitions developmentally timed?
How does Dan function in nuclear architecture? What other genes are regulated in this manner?
What is the biological consequence of nuclear architecture reorganization in attaining neural diversity during brain development?