Megalin-dependent Yellow endocytosis restricts melanization in theDrosophilacuticle

Abstract

SUMMARYThe cuticular exoskeleton of arthropods is a composite material comprising well-separated layers that differ in function and molecular constituents. Epidermal cells secrete these layers sequentially, synthesizing components of distal cuticle layers before proximal ones. Could the order of synthesis and secretion be sufficient to account for the precision with which cuticle components localize to specific layers? We addressed this question by studying the spatial restriction of melanization in the Drosophila wing. Melanin formation is confined to a narrow layer within the distal procuticle. Surprisingly, this tight localization depends on the multi-ligand endocytic receptor Megalin (Mgl). Mgl acts, in part, by promoting endocytic clearance of Yellow. Yellow is required for black melanin formation, and its synthesis begins as cuticle is secreted. Near the end of cuticle secretion, its levels drop precipitously by a mechanism that depends on Mgl and Rab5-dependent endocytosis. In the absence of Mgl, Yellow protein persists at higher levels and melanin granules form ectopically in more proximal layers of the procuticle. We propose that the tight localization of the melanin synthesis machinery to the distal procuticle depends not only on the timing of its synthesis and secretion, but also on the rapid clearance of these components before synthesis of subsequent cuticle layers.

Pigmentation and behavior: potential association through pleiotropic genes in <i>Drosophila</i>

“…This issue is related to the role of Yellow required for the production of black melanin. Recent studies actually support that this enzyme acts downstream of Dopamine as well as that of Dopa suggesting the latter view (Gibert et al, 2007;Riedel et al, 2011). During the immune response, the black melanin produced through DDC activity seems to be the predominant melanization pathway, although a minor path leading to black melanin from Dopa is also implicated (Nappi and Christensen, 2005;Nappi, 2010).…”

“…Simplified schematic models of the proposed biosynthetic pathways in Drosophila. (A) Pathways for producing cuticular pigments, redrawn from figures in Wright (1987), Walter et al (1996), Wittkopp et al (2002Wittkopp et al ( , 2003, True et al (2005), Gibert et al (2007), Kopp (2009), Riedel et al (2011, and Kronforst et al (2012). Some inconsistent views exist about whether the majority of the black melanin is produced from dopa or dopamine (pathways indicated by red broken arrows).…”

Genetic basis of natural variation in body pigmentation inDrosophila melanogaster

“…When mgl expression is reduced, Yellow accumulates, leading to the ectopic formation of abnormally large melanin granules. 15 To our knowledge, this is the first study to associate natural genetic variation in mgl with variation in abdominal pigmentation in D. melanogaster.…”

“…The epidermis modulates the production of black melanin by the exo-and endocytosis of Megalin-dependent vesicles containing Yellow, a protein necessary for dark melanization. 7,15,16 Cell adhesion 17 In conjunction with classical mutant and biochemical analyses, 13,18-23 these studies have pieced together our current understanding of melanin (brown and black coloration) and sclerotin (yellow/ tan coloration) biosynthesis in D. melanogaster (Fig. 1).…”

Endocytic receptor-mediated control of morphogen signaling

“…Yellow is a secreted factor that regulates synthesis of black melanin, a pigment deposited in defined layers of the Drosophila wing. LRP2/Megalin-mediated endocytosis restricts Yellow to distinct layers of the cuticle and controls spatial melanization (Riedel et al, 2011).…”