During peripheral nervous system (PNS) development, axonal growth cones and glial cells commonly migrate for substantial distances; frequently, glia follow the projections of developing axons, suggesting that migration of these two neural elements is coordinated. Silies and Klämbt used deficiency mapping and complementation analysis to show that Drosophila embryos with defects in peripheral glial pattern and migration carried mutations in fzr/cdh1, which encodes Fzr/Cdh1 [fizzy-related, also known as Cdh1, a coactivator of the E3 ubiquitin ligase APC/C (the anaphase-promoting complex, or cyclosome)]. Consistent with Fzr/Cdh1’s role in regulating the cell cycle, the mutant embryos also showed increased numbers of glial cells. However, glial cell number but not their migration was rescued by mutation of cyclinA, which encodes a cell cycle regulator that inhibits Fzr/Cdh1 function, indicating that defects in migration did not depend on defects in the cell cycle. Cell type–specific rescue analyses indicated that Fzr/Cdh1 acted in neurons (rather than glia) to regulate glial migration. fzr/cdh1 mutant motor neurons showed accumulation of an APC/C target, and analyses of embryos with mutations in different APC/C subunits implicated APC/C in glial migration. Glial migration in embryos lacking fzr/cdh1 was substantially rescued by the simultaneous loss of Fasciclin2 [Fas2, a homolog of vertebrate NCAM (neural cell adhesion molecule)], isoforms of which were present in motor neurons and peripheral glia. At the embryonic stage associated with the onset of glial migration, Fas2 formed a gradient in wild-type axons, so that it was more abundant in distal regions and less abundant in regions nearest the central nervous system. This gradient was lost in fzr/cdh1 mutants; moreover, Fas2 overexpression inhibited glial migration. NCAM is targeted for endocytosis by ubiquitination, and inhibition of endocytosis decreased the Fas2 gradient and mimicked the fzr/cdh1 mutant glial migration phenotype. The authors thus propose that APC/CFzr/Cdh1 promotes glial migration in the Drosophila PNS by targeting neuronal Fas2 for endocytosis and thereby creating an axonal gradient of this adhesion molecule.
M. Silies, C. Klämbt, APC/CFzr/Cdh1-dependent regulation of cell adhesion controls glial migration in the Drosophila PNS. Nat. Neurosci. 13, 1357–1364 (2010). [PubMed]