The focus of our laboratory is to identify the mechanisms of cell fate specification during elaboration of the adult peripheral nervous system using the fruit fly, Drosophila melanogaster. During adult neurogenesis, precursor cells undergo several rounds of asymmetric cell division to give rise to an external sensory (ES) organ composed of five distinct cells (fig. 1). The fates of these cells are determined by the activation, or inactivation, of the Notch signaling pathway. In this binary system, a membrane-associated protein Numb, is asymmetrically localized during precursor cell mitosis, and functions as an inhibitor of Notch signaling in the cell that inherits it.
Fig. 1: The ES lineage. At each division (pI, pIIb, pIIa, and pIIIb), Numb (yellow) is asymmetrically localized and segregated to one daughter cell. The divisions occur in an invariant order (pI, then pIIb, then pIIa, then pIIIb) and in set orientations along the body axis. The pI and pIIa divisions occur along the anterior-posterior (A-P) axis and the pIIb and pIIIb divisions occur along the apical-basal (A-B) axis. The cells of the lineage differentiate into a complete external sensory (es) organ.
We are currently using live imaging of proliferating precursors and genetic analysis of mutants to identify genes involved in regulating asymmetric cell division and Numb-mediated inhibition of Notch signaling. Our genetic studies have revealed that a Drosophila cortical tumor suppressor lethal giant larva, or lgl, is required for inhibition of Notch signaling following asymmetric cell division. We are currently pursuing the mechanism of lgl function in this context and are exploring other genes that may play a role in Notch signaling or cell fate specification in the nervous system. These studies have the potential to provide significant insights into common mechanisms of stem and progenitor cell regulation, as well as mis-regulation of proliferation and differentiation that occurs in human cancers.