In Drosophila, the two Netrins (NetA and NetB ) and their receptor Frazzled (Fra) mediate the attraction of embryonic longitudinal glia toward the midline ( von Hilchen et al., 2010). Netrins act as chemoattractants through the DCC/Frazzled family of receptors ( von Hilchen et al., 2010 Lai Wing Sun et al., 2011 Chan et al., 1996 Keino-Masu et al., 1996 Kolodziej et al., 1996 Timofeev et al., 2012) and chemorepellants through the Unc5 receptor family ( Keleman and Dickson, 2001 Labrador et al., 2005). In vertebrates, Netrins secreted by the floor plate cells act differentially on the migrating oligodendrocyte precursor cells and this differential outcome is dependant upon the type of receptors expressed in the migrating cells ( Spassky et al., 2002 Wolf and Friedl, 2009 Jarjour, 2003 Tsai et al., 2003). Netrins, a class of secreted laminin-related extracellular proteins, have been described as chemotropic guidance cues for axons and migrating cells during neural development ( Lai Wing Sun et al., 2011 Harris et al., 1996 Ishii et al., 1992 Kennedy et al., 1994 Mitchell et al., 1996 Serafini et al., 1994). Research progress in recent years has revealed the involvement of chemotropic cues in glia migration ( von Hilchen et al., 2010 Chen et al., 2010 Spassky et al., 2002 Kinrade et al., 2001 Liu et al., 2012). Hence, a thorough understanding of the molecules involved in the process of glia migration may contribute to the development of therapeutics for these pathologies.
Defective glia migration is associated with several human diseases including glial brain tumors and defective regeneration following injury in the nervous system ( Klämbt, 2009 Kocsis and Waxman, 2007 Oudega and Xu, 2006). Glia migrate collectively and over long distances to establish an intricate relationship with neurons. Neurons and glia show mutual reliance in many functional and developmental aspects of biology. Our model includes strict spatial localization of a ligand, a cell autonomously acting receptor and a fate determinant that act coordinately to direct glia toward their final destination. NetrinB but not NetrinA serves as a chemoattractant and Unc5 contributes as a repellant Netrin receptor for glia migration. Thus, the glial determinant also regulates the efficiency of collective migration.
Frazzled expression is induced by the transcription factor Glide/Gcm in a dose-dependent manner. Here, we show that the timely and threshold expression of the Netrin receptor Frazzled triggers the initiation of glia migration in the developing Drosophila wing. Several molecules implicated in cell interactions also control collective migration, but their precise role and the finely tuned expression that orchestrates this complex developmental process are poorly understood.
Collective migration is a complex process that contributes to build precise tissue and organ architecture.