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Epithelial cell detachment: Up to PAR

Cell Migration Gateway (December 2008) | doi:10.1038/cmg084

The serine/threonine kinase PAR1 regulates epithelial apical-basal polarity and is required for cell-cell junction remodelling, which allows border cell detachment and migration during Drosophila melanogaster oogenesis.

Border cells as they detach from the follicle cell epithelium and migrate in between nurse cells in a Drosophila egg chamber. Red - rhodamine-phalloidin staining, Blue - DAPI, Green - GFP expressed in border cells and the cells from which they are detaching.

Image courtesy of Dr Jocelyn Dr Denise Montell, The Johns Hopkins University School of Medicine, Baltimore, USA.

Epithelial cells often need to detach from polarized epithelium in order to migrate. This is an important step during both normal embryonic development and metastasis, but little is known about the mechanisms that underlie this process. In Current Biology, Denise Montell and colleagues now report that cells require the serine/threonine kinase PAR1 to detach from the epithelium.

Drosophila melanogaster oogenesis is widely used as a model for studying cell migration in vivo. Drosophila egg chambers contain one oocyte and 15 nurse cells surrounded by somatic follicle cells that form a monolayer epithelium. At the anterior end of the egg chamber, polar cells recruit several follicle cells to form the border-cell cluster. As egg-chamber development progresses, border cells detach from the surrounding epithelium and migrate as a cohort towards the oocyte.

The authors identified four par1 mutant alleles in a mutagenesis screen aimed at isolating genes involved in border cell migration. Although loss of par1 did not affect border cell-cluster formation, most par1 mutant cells failed to detach from the follicular epithelium. Analysis of egg chambers with par1 mutated only in certain cell types showed that PAR1 activity is required in border cells and possibly in adjacent anterior follicle cells to allow cell detachment.

But how does PAR1 affect detachment? Before detachment, border cells have apical-basal polarity, which is regulated by PAR1 and PAR3 in a manner similar to that of epithelial cells. PAR1 and PAR3 show complementary localisations — PAR1 localises to basolateral membranes, whereas PAR3 accumulates with E-cadherin at the apical junctions between follicle cells and border cells. Loss of par1 results in loss of E-cadherin foci and random distribution of PAR3. PAR1 is known to phosphorylate and inhibit PAR3. Overexpression of a PAR3 mutant that cannot be phosphorylated by PAR1 resulted in border cells failing to detach from the epithelium — a phenotype similar to par1 loss-of-function mutants. Therefore, the restriction of PAR3 to apical domains and its inhibition by PAR1 are required to remodel cell-cell junctions and allow cell detachment.

This study shows that PAR1 functions to remodel specific epithelial cell junctions and allow cell migration. However, other studies have shown that basolateral proteins such as Scribble and Discs-large inhibit detachment. Thus the relationship between apical-basal polarity and epithelial detachment still remains to be fully understood.

Kim Baumann - Copyright © 2008 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission

Original Research Paper

  1. PAR-1 Kinase Regulates Epithelial Detachment and Directional Protrusion of Migrating Border Cells. McDonald , J. A. , Khodyakova , A. , Aranjuez , G. , Dudley , C. and Montell , D. Curr. Biol. 18, 1659–1667 (2008)