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Molecular and Cellular Biology, September 2009, p. 4679-4690, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00297-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Drosophila Metastasis Suppressor Gene Nm23 Homolog, awd, Regulates Epithelial Integrity during Oogenesis{triangledown} ,{ddagger}

Julie A. Woolworth,{dagger} Gouthami Nallamothu,{dagger} and Tien Hsu*

Department of Pathology and Laboratory Medicine and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425

Received 6 March 2009/ Returned for modification 7 April 2009/ Accepted 24 June 2009

The expression levels of the metastasis suppressor gene Nm23 have been shown to correlate positively or inversely with prognosis in different cancer cohorts. This indicates that Nm23 may be needed at different expression levels and may function differently in various tissues. Here we report a novel epithelial function of the Drosophila melanogaster homolog of human Nm23, abnormal wing discs (awd). We show a dynamic expression pattern of the Awd protein during morphogenesis of the Drosophila follicle cells during oogenesis. Loss-of-function awd mutant cells result in the accumulation and spreading of adherens junction components, such as Drosophila E-cadherin, β-catenin/Armadillo, and {alpha}-spectrin, and the disruption of epithelial integrity, including breaking up of the epithelial sheet and piling up of follicle cells. In contrast, overexpression of awd diminishes adherens junction components and induces a mesenchymal-cell-like cell shape change. The gain-of-function phenotype is consistent with a potential oncogenic function of this metastasis suppressor gene. Interestingly, we demonstrate that the epithelial function of awd is mediated by Rab5 and show that the Rab5 expression level is downregulated in awd mutant cells. Therefore, awd modulates the level and localization of adherens junction components via endocytosis. This is the first demonstration of an in vivo function of Nm23 family genes in regulating epithelial morphogenesis.

* Corresponding author. Mailing address: Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas St., Room 330, Charleston, SC 29425. Phone: (843) 792-0638. Fax: (843) 792-5002. E-mail: hsut{at}musc.edu

{triangledown} Published ahead of print on 6 July 2009.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, September 2009, p. 4679-4690, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00297-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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