Specification of temporal identity in neuroblast cell lineages
Producing the right cells at the right time is essential for normal development, yet it is not well understood how an embryonic precursor cell or a stem cell reproducibly generates a characteristic sequence of different cell types. To begin to study this question, we have done comprehensive cell lineage studies to identify the clone of neurons and glia produced by all 30 different embryonic neuroblasts (http://www.neuro.uoregon.edu/doelab/lineages/), as well as the precise birth-order of all progeny for selected neuroblasts.
We recently showed that nearly all of the 30 different Drosophila neuroblasts in each segment sequentially express the transcription factors Hunchback ö Krüppel ö Pdm ö Castor, raising the possibility of a molecular "clock" for distinguishing GMC birth-order (Isshiki et al., 2001, Cell 106:511). Interestingly, while neuroblast only transiently expressed each gene, the daughter GMCs born during each window of expression maintained expression of that gene as they differentiated. Thus, first-born GMCs maintain Hunchback as they differentiate, whereas second-born GMCs maintain Kruppel as they differentiate. Mutant and misexpression studies show that Hunchback is necessary and sufficient for first-born cell fates, whereas Krüppel is necessary and sufficient for second-born cell fates; we observe this in multiple neuroblast lineages and is independent of the cell type involved. We postulate that Hunchback ö Krüppel ö Pdm ö Castor are "temporal coordinate genes" that act together with "spatial coordinate genes" known to specify each neuroblast identity to uniquely specify the identity of each neuron or glia in the CNS.
More recently, Bret Pearson in the lab has shown that Hunchback has the potential to "restart" the lineage of older neuroblasts, revealing a surprising degree of plasticity in neuroblast developmental potential. Bret has also shown that transient expression of Hunchback can produce long-term heritable specification of first-born cell fate, suggesting that Hunchback-mediated chromatin remodeling may be involved in the specification of neuronal temporal identity, similar to the role of Hunchback in establishing heritable HOX gene expression.
Other questions that we are interested in are: Do Pdm an d Castor have similar functions in specifying later-born fates? What regulates the timing of the gene expression "clock" that controls Hunchback ö Krüppel ö Pdm ö Castor? And, do hunchback and Krüppel orthologs have similar functions during vertebrate neurogenesis or hematopoiesis?