Amin S. Ghabrial, Ph.D.
Assistant Professor, Cell and Developmental Biology

Developmental Biology Program

Address

1214 Biomedical Research Bldg. (BRB)
421 Curie Boulevard
Philadelphia, PA 19104

Office tel.: 215 898-7805
Fax: 215 898-9871
E-mail: ghabrial@mail.med.upenn.edu

Links:

Cell and Developmental Biology

Ghabrial Lab

Education

Washington University in Saint Louis: AB, (Biology, English Literature), 1989

University of Texas at Austin: MA, (Zoology), 1991.

Princeton University: PhD, (Molecular Biology), 2000.

Research Interests

• How cells make and shape tubular organs

Key words: Drosophila, Notch, FGF, Cell signaling, morphogenesis, epithelial biology, tubes, tubulogenesis, organogenesis, Rab, RabGAP.

Description of Research

The Drosophila tracheal (respiratory) system is used a simple model tubular organ to uncover the genetic and molecular basis of how tubes are made and shaped.

Branching morphogenesis: One interest in the lab is understanding how cells within an epithelium communicate with each other and change their relative positions so that a new tube will bud and grow out from the epithelium, a process called branching morphogenesis. We have determined that this process is mediated by competition among the cells of the epithelium to lead branch budding and migration in response to a growth factor signal generated by cells outside the epithelium. The competition also involves communication among the cells within the epithelium, in which signaling through Notch is used by the competing cells to inhibit their neighbors. The outcome of the competition is the selection of one or two leading cells per branch, called tip cells, with the other cells becoming followers and making up the stalk of the new tube. Current efforts are directed towards the characterization of a mutation that disrupts the Notch-dependent inhibitory signal (in collaboration with Mark Krasnow's lab at Stanford), and the initiation of a genetic screen to identify additional genes required for tip cell behavior..

Tube morphogenesis: There are three distinct types of tubes in the tracheal system: multicellular tubes formed by cells making intercellular junctions, autocellular tubes formed by cells wrapping around their long axis to make autocellular junctions, and subcellular tubes formed entirely within single cells that generate an internal lumen by a vesicle fusion mechanism. A major focus in the lab is elucidating the cellular and molecular mechanisms that are operative during the formation of these different types of tubes. We are particularly interested in understanding the genetic pathways that drive tube morphogenesis down-stream of growth factor signaling. A "genetic-mosaic" screen has been carried out in which clones of homozygous mutant cells were generated in an otherwise heterozygous animal; this approach has led to identification of ~ 70 genes required for making and shaping tracheal tubes. Currently, several genes affected in mutants recovered in the screen are being positionally cloned; while the molecular functions of other genes that have already been cloned in the lab are being characterized.

Selected Publications

Ghabrial AS, Krasnow MA. (2006). Social interactions among epithelial cells during tracheal branching morphogenesis. Nature. Jun 8;441(7094):746-9.

Levi BP, Ghabrial AS, Krasnow MA. (2006). Drosophila talin and integrin genes are required for maintenance of tracheal terminal branches and luminal organization. Development. Jun;133(12):2383-93.

Ghabrial A, Luschnig S, Metzstein MM, Krasnow MA. (2003). Branching morphogenesis of the Drosophila tracheal system. Annu Rev Cell Dev Biol.;19:623-47.

Search PubMed for more articles

Lab

Rotation Projects

Tube formation projects: Most organs and glands are composed of networks of branched and interconnected tubes. Some of the smallest tubes are formed within single cells by a mysterious process called “cell hollowing.” Examples of such tubes include the seamless endothelial tubes present in the mammalian vascular system as well as the terminal tubes of the Drosophila tracheal system. In a large-scale forward genetic screen carried out in Drosophila, a number of mutations that disrupt cell hollowing were identified. By determining the molecular identity of the genes affected in these mutants we aim to build a molecular understanding of how cells convert themselves into tubes.

1. Positional cloning of cystic lumens. Mutations in cystic lumens cause a striking defect in tube shape: the lumens of mutant cells show areas of constriction and dilation.
2. Positional cloning of impatent. Mutations in impatent disrupt the ability of tracheal terminal cells to make seamless tubes. The mutant cells still branch extensively, acquiring the normal stellate shape of tracheal terminal cells, but they fail to convert their cellular extensions into tubes.
   To identify the genes affected by the cystic lumens and impatent mutations, a positional cloning strategy will be followed. These projects will involve classical and modern genetic mapping techniques as well as molecular biology.

Branching morphogenesis projects: Formation of branched tubular organs often occurs by a process called “branching morphogenesis”. Sprouting angiogenesis in the mammalian vascular system and primary branching of the Drosophila tracheal system both employ this mode of development – in which new tubes bud from the epithelium of pre-existing tubes – to form new branches in their tubular networks. How cells rearrange within an epithelium during the formation of a new tube is not understood, although we have found that it is driven in part by a competition between cells for leading (“tip cell”) positions that divides the cells into leaders and followers. Cells that have been sorted into the stalk of a new tube will continue to alter their arrangement in the epithelium, as they intercalate to form a longer and thinner tube. To understand the cellular and molecular mechanisms which control these morphogenetic movements we will carry out a careful phenotypic and molecular analysis of mutants that disrupt these processes.

1. Live cell imaging of re-arrangement during primary branching. Because branching morphogenesis is a dynamic process, attempting to understand the morphogenetic mechanisms at work by examination of fixed samples is problematic. By taking advantage of the genetic tools available in Drosophila, it will be possible to generate twin spot clones within the tracheal system and watch as the differently marked cells (one daughter marked with green fluorescent protein, the other marked with cherry) move relative to each other within the epithelium during primary branching. In addition, to determining how wild type control twin spots behave, we will be able to examine twin spots in which one daughter is homozygous for a mutant of interest while the other daughter is homozygous wild type.
2. Positional cloning of conjoined. Cells that are mutant for conjoined are defective in rearrangement within the epithelium. This is particularly evident in portions of the tubular network that normally undergo intercalation. At a defined time point in development, these tubes change from shorter wider tubes that are two cells in diameter to longer thinner tubes that are a single cell in diameter. As this occurs, cells that are initially arranged side-by-side move into a head-to-tail configuration. However, if one of the cells is mutant for conjoined, then the cells fail to rearrange and remain side-by-side.

Lab Personnel:

Postdoctoral Fellow:
Jodi Schottenfeld (Ph.D. Princeton University, 2008)

Lab Technician:
Tovah Tripp (B.A. Haverford, 2008)

Undergraduate Researchers:
Allen Ruan (Penn class of 2010)
Ali-Reza Mirsajadi (Penn class of 2011)