Article

A C-Terminal Motif Targets Hedgehog to Axons, Coordinating Assembly of the Drosophila Eye and Brain

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Developmental Cell (Impact Factor: 10.37). 06/2006; 10(5):635-46. DOI: 10.1016/j.devcel.2006.03.003
Source: PubMed

ABSTRACT The developmental signal Hedgehog is distributed to two receptive fields by the photoreceptor neurons of the developing Drosophila retina. Delivery to the retina propagates ommatidial development across a precursor field. Transport along photoreceptor axons induces the development of postsynaptic neurons in the brain. Hedgehog is composed of N-terminal and C-terminal domains that dissociate in an autoproteolytic reaction that attaches cholesterol to the N-terminal cleavage product. Here, we show that the N-terminal domain is targeted to the retina when synthesized in the absence of the C-terminal domain. In contrast to studies that have focused on cholesterol as a determinant of subcellular localization, we find that the C-terminal domain harbors a conserved motif that overrides retinal localization, sending most of the autocleavage products into vesicles bound for growth cones or synapses. Competition between targeting signals at the opposite ends of Hedgehog apparently controls the match between eye and brain development.

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    • "Hedgehog (Hh), epidermal growth factors (EGFs) and Wingless (Wg) also signal at Drosophila neuronal synapses. Photoreceptor neurons in the developing retina, for example, synthesize Hh and EGF/Spitz (Spi) and release them at axonal termini (Fig. 1A,B), where they are picked up by post-synaptic neurons in the brain (Chu et al., 2006; Huang and Kunes, 1996; Yogev et al., 2010). "
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    Development 02/2014; 141(4):729-36. DOI:10.1242/dev.086223 · 6.27 Impact Factor
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    • "There is evidence that the cholesterol moiety affects the intracellular trafficking of Hh, as a mutant form of Hh lacking the cholesterol adduct shows altered subcellular distribution [10]. In addition, the C-terminal domain regulates the subcellular trafficking of Hh in photoreceptor neurons [11]. Various genetic screens in Drosophila have identified only one gene required to release cholesterol-modified Hh from producing cells: the multipass transmembrane protein Dispatched (Disp) [12]. "
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    ABSTRACT: Hedgehog (Hh) proteins are secreted molecules that function as organizers in animal development. In addition to being palmitoylated, Hh is the only metazoan protein known to possess a covalently-linked cholesterol moiety. The absence of either modification severely disrupts the organization of numerous tissues during development. It is currently not known how lipid-modified Hh is secreted and released from producing cells. We have performed a genome-wide RNAi screen in Drosophila melanogaster cells to identify regulators of Hh secretion. We found that cholesterol-modified Hh secretion is strongly dependent on coat protein complex I (COPI) but not COPII vesicles, suggesting that cholesterol modification alters the movement of Hh through the early secretory pathway. We provide evidence that both proteolysis and cholesterol modification are necessary for the efficient trafficking of Hh through the ER and Golgi. Finally, we identified several putative regulators of protein secretion and demonstrate a role for some of these genes in Hh and Wingless (Wg) morphogen secretion in vivo. These data open new perspectives for studying how morphogen secretion is regulated, as well as provide insight into regulation of lipid-modified protein secretion.
    PLoS ONE 03/2012; 7(3):e33665. DOI:10.1371/journal.pone.0033665 · 3.23 Impact Factor
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    • "ydbio.2010.12.016 in the brain—the lamina. Photoreceptor neurons secrete the Hh signal, followed by Spi, from their axonal termini, triggering neurogenesis in lamina precursor cells (Chu et al., 2006; Huang and Kunes, 1996; Huang et al., 1998). Thus, the Spi processing machinery is employed at two distinct locations within the same cell: initially within the cell body to pattern the ommatidia, and later at the distant axonal growth cones. "
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