Once the team discovered that apontic is important for getting these cells to move, they set out to figure out how apontic works. Collaborating with mathematician Hans Meinhardt, Ph.D., a professor emeritus at the Max Planck Institute in Germany, they designed a computer model that could simulate how graded signals are converted to commands that tell cells to move or to stay.

 

By making certain assumptions about each gene and assigning functions to each protein, the team built a simple circuit that can predict a cell’s behavior using the graded signal, apontic, and another previously discovered protein called slbo (pronounced “slow-bo”). The computer model shows that in a cell, the graded signal turns on both apontic and slbo. But apontic and slbo work against and battle each other: when one gains a slight advantage, the other weakens, which in turn causes the first to gain an even bigger advantage. This continues until one dominates in each cell. If slbo wins, the cell moves but if apontic wins, the cell stays put; thus a clear separation between move or stay is achieved. 

 

“Not only is this a new solution to the problem of how to create a pattern out of no pattern, but we have also discovered that apontic is a new regulator of cell migration,” says Montell.

 

 

The majority of cancers derive from epithelial cells. However these cells only become truly dangerous when they detach from the epithelium of origin and migrate through surrounding tissue until they reach the bloodstream.

 

Only then can the cancerous cells be disseminated to distant sites resulting in metastasis. This behavior seems to mimic that of a variety of embryonic cells which undergo so-called epithelial to mesenchymal transitions.

 

Such transitions are critical to the development of virtually every organ and tissue in the body, especially for example the peripheral nervous system which derives from the neural crest.

 

Yet this cellular behavior remains poorly understood at a mechanistic level. It is likely that epithelial to mesenchymal transitions require alterations in patterns of transcription, in cell adhesion, and in the organization of the cytoskeleton. Our goal is to apply a systematic genetic approach in Drosophila to identify the genes that are required to transform a cell from being part of a stationary epithelium to a migratory state.

 

Text and illustration courtesy of Denise Montell, Ph.D.

 

 

[N1] The research was funded by the American Cancer Society (ACS) and the National Institutes of Health (NIH).

[N2] Denise Montell's laboratory at Johns Hopkins University studies invasive cell behavior using molecular biology, genetics, cell biology, and biochemistry. Her laboratory has established the border cells in the Drosophila ovary as a model system for a systematic, forward genetic approach to study invasive cell behavior and epithelial to mesenchymal transitions.

[N3] Authors on the paper: Michelle Starz-Gaiano, Mariana Melani, Xiaobo Wang, and Denise J. Montell, all of Johns Hopkins University (Baltimore, MD, USA); Hans Meinhardt of the Max-Planck-Institut (Tübingen, Germany).

 

Feedback Inhibition of JAK/STAT Signaling by Apontic Is Required to Limit an Invasive Cell Population. Michelle Starz-Gaiano, Mariana Melani, Xiaobo Wang, Hans Meinhardt, and Denise J. Montell. Developmental Cell 2008 14(6): 726-738.

Summary

In both normal development and in a variety of pathological conditions, epithelial cells can acquire migratory and invasive properties. Border cells in the Drosophila ovary provide a genetically tractable model for elucidating the mechanisms controlling such behaviors. Here we report the identification of a mutant, apontic (apt), in which the migratory population expanded and separation from the epithelium was impeded. This phenotype resembled gain-of-function of JAK/STAT activity. Gain-of-function of APT also mimicked loss of function of STAT and its key downstream target, SLBO. APT expression was induced by STAT, which bound directly to sites in the apt gene. The data suggest that a regulatory circuit between STAT, APT, and SLBO functions to convert an initially graded signal into an all-or-nothing activation of JAK/STAT and thus to proper cell specification and migration. These findings are supported by a mathematical model, which accurately simulates wild-type and mutant phenotypes.