Epithelial to mesenchymal transitions and cell migration

Epithelial to mesenchymal transitions are prominent features of mammalian gastrulation and neural crest development, and are essential for the proper development of many organs and tissues. Moreover, most cancers derive from epithelial cells, and metastasis involves departure of these cells from their epithelium of origin and invasion of the surrounding tissue. It is known that epithelial to mesenchymal transitions involve alterations in gene expression, cell-cell adhesion and actin organization, however, our understanding of this process at a mechanistic level remains incomplete (reviewed in Thiery and Chopin, 1999). The border cells in the Drosophila ovary form a group of six to ten cells that originate from the anterior pole of the follicular epithelium (Fig. 1A). During oogenesis the border cells delaminate from this epithelium and invade the neighboring cluster of germline cells. The border cells migrate approximately 150 μm over the course of 5-6 hours, stopping when they reach the anterior border of the oocyte. A number of mutants have been identified that exhibit defects in border cell migration (reviewed in Montell, 1999). The first such mutation identified was slow border cells (slbo) (Montell et al., 1992), a locus that encodes the Drosophila homolog of the CCAAT enhancer binding protein (C/EBP). Although null mutations in the slbo locus cause lethality in late embryonic or early larval life, P-element insertions into the 5′ region of the gene lead to female sterility. The ovarian phenotype is quite specific; the only apparent defect is delay or failure of border cell migration. The Drosophila C/EBP protein is expressed in the border cells just prior to their migration, consistent with a requirement for C/EBP for the initiation of border cell migration. One critical downstream target of C/EBP is shotgun (shg), the gene that encodes Drosophila E-cadherin (Niewiadomska et al., 1999), which is a homophilic cell-cell adhesion molecule. DE-cadherin expression is elevated during border cell migration, and the increase in expression is C/EBP dependent. E-cadherin is expressed on the surfaces of all of the cells of the egg chamber, and normal border cell migration depends upon both nurse cell and border cell DE-cadherin (Niewiadomska et al., 1999). Shg is not the only relevant downstream target of C/EBP however, as elevating shg expression using a transgene cannot rescue the slbo migration defects, even mild defects associated with hypomorphic alleles. Regulation of the actin cytoskeleton accompanies both epithelial to mesenchymal transitions in general, and border cell migration in particular. The Rho family GTPases are well known for their ability to stimulate dramatic reorganization of the actin cytoskeleton, and one of the Rho family members, 321 Development 128, 321-330 (2001) Printed in Great Britain © The Company of Biologists Limited 2001 DEV8772