Development of the Central Nervous System;
Gene regulation

Telephone: (919) 962-4380 (Office);
(919) 962-3155 (Lab); (919) 962-8472 (Fax)

E-mail: steve_crews@unc.edu

Office: 322 Fordham Hall

Mailing Address:
CB# 3280, Coker Hall
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599-3280

Selected References | Teaching | Curriculum Vitae | Lab Members | Lab Home Page

• Single-minded: Tango and CNS midline cell development
• bHLH-PAS proteins: physiological and developmental regulators of gene transcription
• Midline Fasciclin and control of axon guidance
• Evolution of tissues and regulatory genes

Development of a functional adult organism requires both a series of precisely-controlled molecular events and the ability of embryonic cells to modulate their responses to environmental and physiological stimuli. Our laboratory is concerned with the molecular mechanisms that govern the development of the CNS, including: (1) how different classes of nerve and glial cells form, and (2) how neuronal axons find their synaptic targets. The lab is focused on studying the cells that lie along the midline of the Drosophila CNS, since they represent a relatively simple, but important, group of cells. We are also concerned with how cells respond to different physiological conditions, such as oxygen levels, and alter their developmental and physiological responses. Many of these developmental events are mediated by factors that control transcription, and consequently the lab as studied, in great detail, a family of important development and physiological regulatory proteins, the basic-helix-loop-helix-PAS (bHLH-PAS) proteins. We also study members of the Fasciclin I family of cell adhesion/secreted axon guidance molecules.

CNS midline cells (green) and subset of lateral CNS cells (red)

Single-minded: Tango and CNS midline cell development. The Drosophila CNS midline cells are an important signaling center that control numerous developmental events including CNS axon guidance. They also constitute a set of functional neurons and glia. The Single-minded:Tango bHLH-PAS proteins are regulators of CNS midline cell specification. They act as genetic switch that triggers neuroectodermal cells into forming CNS midline cells. Current work is involved with understanding how the Single-minded:Tango protein complex acts with additional transcription factors to control specific midline cell fates. For instance, Single-minded:Tango interacts with the Drifter and Fish-hook transcription factors to control midline glial gene expression. We would like to understand at both genetic and biochemical levels how other transcription factors and signaling pathways interact with Single-minded:Tango to control midline neuron formation. In addition, microarray technology and other approaches are being utilized to identify genes involved in CNS midline cell development, and understand their function and regulation.

bHLH-PAS proteins: physiological and developmental regulators of gene transcription. bHLH-PAS proteins are an evolutionarily-conserved family of proteins that control a variety of biological events including: circadian rhythms, toxin metabolism, tissue-specific development, hypoxia, and hormone responsiveness. The Tango bHLH-PAS protein is the dimerization partner of Single-minded, Trachealess, Spineless, Similar, and Cranky. The Similar protein resembles mammalian Hypoxia inducible factors (HIFs) and likely controls the response to oxygen deprivation in Drosophila. When oxygen levels are normal, HIF proteins are degraded. When oxygen levels are low, HIF proteins dimerize with Tango (Drosophila) or ARNT (vertebrates) and activate genes involved in the response to hypoxia. In mammals, the HIF proteins are important in tumor growth, blood vessel formation, and the neural control of respiration. In insects, one function of HIF proteins is to control tracheal branching, and practical applications include the creation of less toxic insecticides. Our lab is concerned with the genetics and biochemistry of hypoxia regulation in insects. This includes identifying oxygen-sensing components that regulate hypoxia-mediated transcription and identifying genes controlled by oxygen levels. We have also identified Cranky, a novel bHLH-PAS protein expressed in a number of embryonic cell types, and its function is being studied using genetic methods.

Midline Fasciclin and control of axon guidance. Both Fasciclin I and Midline fasciclin have been implicated in controlling Drosophila axon guidance. They constitute a small, but unique, set of Drosophila proteins with a structure consisting of four extracellular repeats. Midline fasciclin is a membrane-associated protein, and particularly interesting since it is expressed only in the CNS midline cells. Current work is involved with determining whether Fasciclin I and Midline fasciclin interact to control axonogenesis, and the identification of additional guidance signaling molecules that may interact with Midline fasciclin.

Evolution of tissues and regulatory genes. One of the most interesting issues facing developmental biologists is how different tissues and cell types have evolved. With the discovery of a large number of important regulatory genes in model organisms, such as Drosophila, it has become possible to address these issues. The bHLH-PAS proteins are master regulators of CNS midline cell and trachea development in Drosophila, and also participate in the formation of other cell types. We have begun to identify orthologs of these genes in other arthropods and study how they control development of related tissue types.