The Drosophila transmembrane protein Fear-of-intimacy controls glial cell migration

Abstract

Development of complex organs depends on intensive cell-cell interactions, which help coordinate movements of many cell types. In a genetic screen aimed to identify genes controlling midline glia migration in the Drosophila nervous system, we have identified mutations in the gene kastchen. Here we show that during embryogenesis kastchen is also required for the normal migration of longitudinal and peripheral glial cells. During larval development, kastchen non-cell autonomously affects the migration of the subretinal glia into the eye disc. During embryonic development, kastchen not only affects glial cell migration but also controls the migration of muscle cells toward their attachment sites. In all cases, kastchen apparently functions in terminating or restricting cell migration. We identified the molecular nature of the gene by performing transgenic rescue experiments and by sequence analysis of mutant alleles. Kastchen corresponds to the recently described gene fear-of-intimacy (foi) that was identified in screen for genes affecting germ cell migration, suggesting that Foi-Kastchen is more generally involved in regulating cell migration. It encodes a member of an eight-transmembrane domain protein family of putative Zinc transporters or proteases. We determined the topology of the Foi protein by using antisera against luminal and intracellular domains of the protein and provide evidence that it does not act as a Zinc transporter. Genetic evidence suggests that one of the functions of foi may be associated with hedgehog signaling.

Glial Cell Migration in the Eye Disc

“…Thus, neuronal cells are sufficient, but not necessary to regulate glial migration. In agreement with this notion are reports that document glial migration independent of axons as seen in gilgamesh, hedgehog or fear of intimacy mutants (Hummel et al, 2002;Pielage et al, 2004).…”

Fear-of-intimacy mediated zinc transport controls the function of Zn-finger transcription factors involved in myogenesis

“…It was already known that the zinc transport activity of Foi is essential for gonadal development (Mathews et al, 2006). Our data indicate that, in addition to its role in gonads, trachea and glial cells (Pielage et al, 2004;Van Doren et al, 2003), Foi is necessary for the normal development of somatic and visceral muscles. Although in foi mutants gastrulation is not affected and the different subtypes of somatic and visceral myoblasts segregate normally, these are not well specified.…”

“…ZIP transporters with different subcellular localizations, or zinc transporters of the ZnT family, which act in the opposite direction and deplete the cytoplasmic supply of zinc, would probably not replace Foi. However, if in the mesoderm Foi's role is unrelated to its function as a regulator of zinc homeostasis, as previously suggested for Foi in controlling glial cell migration (Pielage et al, 2004), none of the known Drosophila zinc transporters should rescue the absence of foi.…”

“…1F). Although it is known that foi participates in gonad formation, tracheal branch fusion and glial cell migration (Mathews et al, 2006;Pielage et al, 2004;Van Doren et al, 2003), its requirement for myogenesis has not been investigated in depth. The expression of Myosin in foi C887 and foi C153 mutant embryos showed a defective muscle pattern with missing muscles, morphological defects in dorsal, lateral and ventral groups of muscles, and a fusion defect, visualized by the reduced size of the remaining muscles (Fig.…”

“…In a Drosophila genetic screen performed to identify novel genes required for myoblast specification and differentiation, we isolated two new alleles of fear-of-intimacy ( foi), a gene that has been implicated in the processes of gonad and trachea morphogenesis and glial cell migration (Mathews et al, 2006;Pielage et al, 2004;Van Doren et al, 2003). foi encodes a protein of the ZIP (Zrt/IRT-like or solute carrier 39A, SLC39A) family of ion transporters (related to the vertebrate LIV-1 subfamily) that has specificity for zinc and localizes to the basolateral cell membrane (Lye et al, 2013;Mathews et al, 2005).…”