Research Summary:

How does a complex organism - composed of numerous differentiated cell types and integrated organ systems - develop from a fertilized egg? We are using the fruit fly, Drosophila melanogaster, as a model system to address this fundamental question of developmental biology. Our studies probe basic mechanisms underlying pattern formation, determination, differentiation and morphogenesis in animal development. The two major projects currently underway in the lab are summarized below.

The first major project in the lab is to study how a group of master regulatory genes - the homeobox (Hox) genes - establishes the basic body plan of the fly during early embryogenesis. Hox genes specify cell fate and regional identity during animal development. These genes are structurally and functionally conserved throughout the animal kingdom: we and others have shown that Hox genes from mammals and flies are functionally equivalent in that mammalian Hox genes can mimic the function of fly homologs when expressed as transgenes in Drosophila. Hox genes encode DNA binding proteins that act as molecular switches for transcription, turning on the expression of groups of downstream target genes during embryogenesis. Hox proteins select these target genes in the genome by interacting with specific protein partners or cofactors. We are studying the regulation and function of the Hox gene fushi tarazu (ftz). We discovered that Ftz interacts with a novel cofactor - the orphan nuclear receptor Ftz-F1. Ftz and Ftz-F1 bind cooperatively to DNA to coordinately regulate target gene expression. Studies underway in the lab focus on: isolation of transcription factors that regulate ftz gene expression; analysis of how Ftz and Ftz-F1 interact to regulate transcription; bioinformatics approaches to identify downstream targets of the Ftz/Ftz-F1 protein complex; studies of novel mechanisms regulating Ftz-F1 nuclear receptor activity in the embryo; and investigation of how specific functions of Ftz and other Hox proteins have been acquired during the course of evolution of invertebrates and vertebrates.

A second major project in the lab is to study how neuronal connections are established in the central nervous system during development. Normal function of the nervous system requires the formation of numerous precise connections between axons and their targets. How do axons find these targets? We have recently discovered that the Drosophila insulin receptor (DInR) functions as an axon guidance receptor in the developing visual system. DInR directs the formation of precise neuronal connections between the retina and brain, resulting in a highly ordered retinotopic map that allows the animal to decode visual input from the environment to "make sense" of the world. DInR regulates axon guidance via direct physical interaction with the SH2/SH3 adapter protein Dock. Dock in turn signals through p21-activated kinase (Pak), to cause changes in actin cytoskeleton which promote axonal migration. Our findings suggest a general role for the insulin receptor family in regulating axon guidance throughout the animal kingdom. We are currently investigating the role of DInR in regulating axon targeting; studying the requirements for its interaction with Dock and other signaling partners; and initiating studies to identify the ligand(s) that regulate DInR activity in the central nervous system. In the long term, these studies will contribute to our understanding of mechanisms underlying neuronal insulin receptor control of eating behavior, learning and memory in both invertebrates and vertebrates.

Publications:

Zhao, J.J., Lazzarini, R.A. and Pick, L. (1996). Functional dissection of the mouse Hox-a5 gene.
EMBO J. 15: 1313-1322.

Yu, Y., Li, W., Su, K., Han, W., Yussa, M. and Pick, L. (1997). The nuclear hormone receptor FTZ-F1 is a
cofactor for the Drosophila homeodomain protein Ftz. Nature 358: 552-555.

Han, W., Yu, Y., Kohanski, R.A. and Pick, L. (1998). An essential site in the ftz proximal enhancer interacts
with multiple transcriptional activators. Mol. Cell. Biol. 18: 3384-3394.

Pick, L. (1998). Segmentation: painting stripes from flies to vertebrates. Dev. Genet. 23: 1-10.

Lawrence, P.A. and Pick, L. (1998). How does the fushi tarazu gene activate engrailed in the Drosophila
embryo? Dev. Genet. 23: 28-34.

Yu, Y., Yussa, M., Song, J., Hirsch, J. and Pick, L. (1999). A Double Interaction Screen identifies positive
and negative ftz gene regulators and Ftz-interacting protein. Mech. Dev., 83: 95-105.

Pick, L., Lohr, U. and Yu, Y. (2000). A Double Interaction Screen to isolate DNA binding and protein
tethered transcription factors. In "Yeast Hybrid Techniques - genetic assay system for protein
interactions." Ed. L. Zhu and G.J. Hannon. Eaton Publishing, Natick, MA.

Yussa, M., Lohr, U., Su, K. and Pick, L. (2001). The nuclear receptor Ftz-F1 and homeodomain protein Ftz
interact through evolutionarily conserved protein domains. Mech. Dev., 107: 39-53.

Lohr, U., Yussa, M. and Pick, L. (2001) Drosophila fushi tarazu: a gene on the border of homeotic function.
Current Biology (Cell Press), 11:1 403-1412.

Song, J., Wu, L., Chen, Z., Kohanski, R.A. and Pick, L. (2003) Axons guided by Insulin Receptor in the Drosophila Visual System. Science 300: 502 - 505. Additional online Supplementary Material.