Overview
Research in my laboratory focuses on how two signaling pathways collaborate to establish neuroectodermal cell fates in the Drosophila blastoderm embryo. The neuroectoderm, which comprises the lateral region of the blastoderm embryo, gives rise to both neuronal and epidermal cell types. Two early acting genes expressed in the neuroectoderm are short gastrulation (sog) and rhomboid (rho). sog encodes a secreted factor antagonist (Sog) of the TGF-§ family member Dpp (François et al., 1994). Dpp signaling promotes epidermal fates and suppresses the default development pathway of neurogenesis. Sog provides a permissive condition for neurogenesis by acting as an anti-neural inhibitor. The antagonistic relationship between Sog and Dpp has been highly conserved during evolution. Chordin, the vertebrate homologue of Sog (François and Bier, 1995), is an endogenous neural inducer produced by the Spemann organizer which functions by antagonizing the neural suppressive activity of BMP-4 (the vertebrate homologue of Dpp). Furthermore, Sog mimics the activity of Chordin in Xenopus embryos (Schmidt et al., 1995) and vice versa, and Dpp and BMP-4 are functionally interchangeable in frogs and flies.
The rho gene (Bier et al., 1990) encodes an integral membrane protein (Rho) (Sturtevant et al., 1996) which potentiates EGF-R signaling (Sturtevant et al., 1993; Noll et al., 1994). rho is expressed in localized patterns corresponding to cells requiring high levels of EGF-R activity during embryonic (Bier et al., 1990) and adult development (Sturtevant et al., 1993). Since low levels of EGF-R signaling are essential for the viability of nearly all epidermal cells, localized hyperactivation of EGF-R signaling by Rho permits the ubiquitously active EGF-R pathway to be used for discrete developmental purposes. rho and sog mutants interact synergistically indicating that specification of the neuroectoderm depends on a combination of hyperactive EGF-R signaling and attenuated Dpp signaling. Ultimately, the neuroectoderm gives rise to neuronal precursor cells expressing transcription factors such as deadpan (dpn) (Bier et al., 1992) and scratch (scrt) (Roark et al., 1995; Emery and Bier, 1995).
In addition to their roles during early embryogenesis, the Dpp (Yu et al., 1996) and EGF-R (Sturtevant et al. 1993; Noll et al., 1994) pathways function during metamorphosis to make the binary vein versus intervein cell fate choice. The wing is ideal for studying interactions between these two signaling pathways as it is a substantially less complicated structure than the embryo. Additionally, analysis of the many existing vein mutants reveals a variety of cell-cell signaling events required for making and maintaining the vein versus intervein cell fate choice (Sturtevant and Bier, 1995). rho dependent EGF-R signaling promotes vein formation throughout larval and early pupal development. One function of rho is to induce expression of dpp in vein primordia. sogis expressed in intervein cells and functions to block Dpp activity in intervein cells (Yu et al., 1996). While the Dpp and EGF-R pathways collaborate to promote vein formation during wing development, it is noteworthy that these two pathways exert opposing functions during early neurogenesis. Future genetic analyses will exploit the various strengths of the embryo and wing to further characterize interactions between the Dpp and EGF-R signaling and to identify new genes participating in these two pathways.
An important goal of current and future studies in my laboratory is to determine the biochemical mechanisms underlying the genetic phenomena we have characterized. For example, a key question regarding the function of the Sog protein is whether Sog is proteolytically processed from the primary predicted protein precursor and whether such peptides would retain or lose the ability to inactivate components of the Dpp signaling pathway. In the case of rho, one important goal is to identify proteins physically interacting with Rho, and to determine how Rho and other proteins facilitate EGF-R signaling. Ultimately, I seek a synthesis of genetic and biochemical analyses to provide a detailed understanding of how crude positional information is converted into the differentiation of final specialized structures.
Areas of Research
Embryonic dorsal-ventral patterning
