{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T12:18:57Z","timestamp":1789733937661,"version":"4.0.1"},"reference-count":54,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2016,12,15]],"date-time":"2016-12-15T00:00:00Z","timestamp":1481760000000},"content-version":"vor","delay-in-days":349,"URL":"http:\/\/www.biologists.com\/user-licence-1-1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 GM110015"],"award-info":[{"award-number":["RO1 GM110015"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003443","name":"Ministry of Education and Science of the Russian Federation","doi-asserted-by":"publisher","award":["14.B25.31.0022"],"award-info":[{"award-number":["14.B25.31.0022"]}],"id":[{"id":"10.13039\/501100003443","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Legacy Heritage Bio-Medical Program of the Israel Science Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:p>Coalescence of the embryonic gonad in Drosophila melanogaster requires directed migration of the primordial germ cells (PGCs) towards the somatic gonadal precursor cells (SGPs). It was recently proposed that an ATP-Binding Cassette (ABC) transporter, Mdr49, functions in the embryonic mesoderm to facilitate the transmission of the PGC attractant from the SGPs; however, the precise molecular identity of the mdr49 dependent guidance signal remained elusive. Employing the \u2018loss\u2019 and \u2018gain\u2019 of function strategies we show that mdr49 is a component of the hh pathway and it potentiates the signaling activity. This function is direct as, in mdr49 mutant embryos, Hh ligand is inappropriately sequestered in the hh expressing cells. Our data also suggest that role of Mdr49 is to provide cholesterol for the correct processing of the Hh precursor protein. Supporting this conclusion, PGC migration defects in mdr49 embryos are substantially ameliorated by a cholesterol-rich diet.<\/jats:p>","DOI":"10.1242\/dev.133587","type":"journal-article","created":{"date-parts":[[2016,4,28]],"date-time":"2016-04-28T16:33:53Z","timestamp":1461861233000},"source":"Crossref","is-referenced-by-count":9,"title":["Functioning of an ABC transporter, Mdr49, in Hh signaling and germ cell migration"],"prefix":"10.1242","author":[{"given":"Girish","family":"Deshpande","sequence":"first","affiliation":[{"name":"Department of Molecular biology, Princeton University, Princeton NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Manry","sequence":"additional","affiliation":[{"name":"Department of Molecular biology, Princeton University, Princeton NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Jourjine","sequence":"additional","affiliation":[{"name":"Department of Molecular biology, Princeton University, Princeton NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladic","family":"Mogila","sequence":"additional","affiliation":[{"name":"Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henny","family":"Mozes","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Cancer Research, IMRIC, The Hebrew University, 91120 Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzofia","family":"Bialistoky","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Cancer Research, IMRIC, The Hebrew University, 91120 Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Offer","family":"Gerlitz","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Cancer Research, IMRIC, The Hebrew University, 91120 Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Schedl","sequence":"additional","affiliation":[{"name":"Department of Molecular biology, Princeton University, Princeton NJ 08540, USA"},{"name":"Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608273846900_DEV133587C1","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1038\/368208a0","article-title":"Compartment boundaries and the control of Drosophila limb pattern by Hedgehog protein","volume":"368","author":"Basler","year":"1994","journal-title":"Nature"},{"key":"2021042608273846900_DEV133587C2","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1242\/dev.121.6.1815","article-title":"Specification, migration and assembly of the somatic-cells of the Drosophila gonad","volume":"121","author":"Boyle","year":"1995","journal-title":"Development"},{"key":"2021042608273846900_DEV133587C3","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1242\/dev.124.5.971","article-title":"Expression and function of clift in the development of somatic gonadal precursors within the Drosophila mesoderm","volume":"124","author":"Boyle","year":"1997","journal-title":"Development"},{"key":"2021042608273846900_DEV133587C4","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/nrm3598","article-title":"The mechanisms of Hedgehog signalling and its roles in development and disease","volume":"14","author":"Briscoe","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021042608273846900_DEV133587C5","doi-asserted-by":"publisher","first-page":"12591","DOI":"10.1073\/pnas.1106881108","article-title":"Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium","volume":"108","author":"Callejo","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608273846900_DEV133587C6","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/S0092-8674(03)00199-5","article-title":"The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance","volume":"113","author":"Charron","year":"2003","journal-title":"Cell"},{"key":"2021042608273846900_DEV133587C7","doi-asserted-by":"publisher","first-page":"3226","DOI":"10.1111\/j.1742-4658.2011.08235.x","article-title":"Multidrug resistance proteins (MRPs\/ABCCs) in cancer chemotherapy and genetic diseases","volume":"278","author":"Chen","year":"2011","journal-title":"FEBS J."},{"key":"2021042608273846900_DEV133587C8","first-page":"5","article-title":"ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal","volume":"4","author":"Choi","year":"2005","journal-title":"Cancer Cell Int."},{"key":"2021042608273846900_DEV133587C9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0022-2275(20)40254-8","article-title":"The utilization of sterols by insects","volume":"15","author":"Clayton","year":"1964","journal-title":"J. Lipid Res."},{"key":"2021042608273846900_DEV133587C10","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.devcel.2005.09.014","article-title":"HMGCoA reductase potentiates hedgehog signaling in Drosophila melanogaster","volume":"9","author":"Deshpande","year":"2005","journal-title":"Dev. Cell"},{"key":"2021042608273846900_DEV133587C11","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/S0092-8674(01)00488-3","article-title":"Hedgehog signaling in germ cell migration","volume":"106","author":"Deshpande","year":"2001","journal-title":"Cell"},{"key":"2021042608273846900_DEV133587C12","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1534\/genetics.107.071415","article-title":"toutvelu, a regulator of heparan sulfate proteoglycan biosynthesis, controls guidance cues for germ-cell migration","volume":"176","author":"Deshpande","year":"2007","journal-title":"Genetics"},{"key":"2021042608273846900_DEV133587C13","doi-asserted-by":"publisher","first-page":"e1000333","DOI":"10.1371\/journal.pgen.1000333","article-title":"G gamma 1, a downstream target for the hmgcr-isoprenoid biosynthetic pathway, is required for releasing the hedgehog ligand and directing germ cell migration","volume":"5","author":"Deshpande","year":"2009","journal-title":"PLoS Genet."},{"key":"2021042608273846900_DEV133587C14","doi-asserted-by":"publisher","first-page":"e1003720","DOI":"10.1371\/journal.pgen.1003720","article-title":"The hedgehog pathway gene shifted functions together with the hmgcr-dependent isoprenoid biosynthetic pathway to orchestrate germ cell migration","volume":"9","author":"Deshpande","year":"2013","journal-title":"PLoS Genet."},{"key":"2021042608273846900_DEV133587C15","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1146\/annurev.biochem.68.1.157","article-title":"Sterols and isoprenoids: Signaling molecules derived from the cholesterol biosynthetic pathway","volume":"68","author":"Edwards","year":"1999","journal-title":"Annu. Rev. Biochem."},{"key":"2021042608273846900_DEV133587C16","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/358387a0","article-title":"Induction of germ cell formation by oskar","volume":"358","author":"Ephrussi","year":"1992","journal-title":"Nature"},{"key":"2021042608273846900_DEV133587C17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1242\/dev.121.1.1","article-title":"Positional signaling by hedgehog in Drosophila imaginal disc development","volume":"121","author":"Felsenfeld","year":"1995","journal-title":"Development"},{"key":"2021042608273846900_DEV133587C18","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1534\/genetics.105.046565","article-title":"Mutations of a Drosophila NPC1 gene confer sterol and ecdysone metabolic defects","volume":"172","author":"Fluegel","year":"2006","journal-title":"Genetics"},{"key":"2021042608273846900_DEV133587C19","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/nrm2720","article-title":"Collective cell migration in morphogenesis, regeneration and cancer","volume":"10","author":"Friedl","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021042608273846900_DEV133587C20","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.tcb.2010.12.005","article-title":"Hedgehog morphogen: from secretion to reception","volume":"21","author":"Gallet","year":"2011","journal-title":"Trends Cell Biol."},{"key":"2021042608273846900_DEV133587C21","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S1534-5807(03)00031-5","article-title":"Cholesterol modification of Hedgehog is required for trafficking and movement, revealing an asymmetric cellular response to Hedgehog","volume":"4","author":"Gallet","year":"2003","journal-title":"Dev. Cell"},{"key":"2021042608273846900_DEV133587C22","doi-asserted-by":"publisher","first-page":"10347","DOI":"10.1073\/pnas.162366399","article-title":"The multidrug transporter, P-glycoprotein, actively mediates cholesterol redistribution in the cell membrane","volume":"99","author":"Garrigues","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608273846900_DEV133587C23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1023\/A:1008023629269","article-title":"Molecular analysis of the multidrug transporter, P-glycoprotein","volume":"27","author":"Germann","year":"1998","journal-title":"Cytotechnology"},{"key":"2021042608273846900_DEV133587C24","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.devcel.2005.01.003","article-title":"Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog","volume":"8","author":"Glise","year":"2005","journal-title":"Dev. Cell"},{"key":"2021042608273846900_DEV133587C25","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.devcel.2004.12.018","article-title":"The Drosophila ortholog of the human Wnt inhibitor factor Shifted controls the diffusion of lipid-modified Hedgehog","volume":"8","author":"Gorfinkiel","year":"2005","journal-title":"Dev. Cell"},{"key":"2021042608273846900_DEV133587C26","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1093\/genetics\/156.4.1777","article-title":"Directed mutagenesis screen in Drosophila melanogaster reveals new mutants that influence hedgehog signaling","volume":"156","author":"Haines","year":"2000","journal-title":"Genetics"},{"key":"2021042608273846900_DEV133587C27","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1146\/annurev.cb.08.110192.000435","article-title":"ABC transporters: from microorganisms to man","volume":"8","author":"Higgins","year":"1992","journal-title":"Annu. Rev. Cell Biol."},{"key":"2021042608273846900_DEV133587C28","doi-asserted-by":"publisher","first-page":"5115","DOI":"10.1242\/dev.02079","article-title":"A Drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis","volume":"132","author":"Huang","year":"2005","journal-title":"Development"},{"key":"2021042608273846900_DEV133587C30","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1101\/gad.938601","article-title":"Hedgehog signaling in animal development: paradigms and principles","volume":"15","author":"Ingham","year":"2001","journal-title":"Genes Dev."},{"key":"2021042608273846900_DEV133587C31","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1242\/dev.120.1.83","article-title":"Primordial germ cell migration in Drosophila melanogaster is controlled by somatic tissue","volume":"120","author":"Jaglarz","year":"1994","journal-title":"Development"},{"key":"2021042608273846900_DEV133587C32","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.devcel.2008.11.010","article-title":"Hedgehog signaling in development and cancer","volume":"15","author":"Jiang","year":"2008","journal-title":"Dev. Cell"},{"key":"2021042608273846900_DEV133587C33","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1146\/annurev.cellbio.22.010305.103337","article-title":"In vivo migration: a germ cell perspective","volume":"22","author":"Kunwar","year":"2006","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2021042608273846900_DEV133587C34","doi-asserted-by":"publisher","first-page":"2634","DOI":"10.1074\/jbc.271.5.2634","article-title":"Role of multidrug resistance P-glycoproteins in cholesterol biosynthesis","volume":"271","author":"Metherall","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021042608273846900_DEV133587C35","first-page":"527","article-title":"Physiological feedback regulation of cholesterol biosynthesis: Role of translational control of hepatic HMG-CoA reductase and possible involvement of oxylanosterols","volume":"39","author":"Ness","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"2021042608273846900_DEV133587C36","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1007\/s00018-005-5554-9","article-title":"P-glycoprotein and \u2018lipid rafts\u2019: some ambiguous mutual relationships (floating on them, building them or meeting them by chance?)","volume":"63","author":"Orlowski","year":"2006","journal-title":"Cell. Mol. Life Sci."},{"key":"2021042608273846900_DEV133587C37","doi-asserted-by":"publisher","first-page":"24020","DOI":"10.1074\/jbc.R114.583658","article-title":"Molecular mechanisms of cellular cholesterol efflux","volume":"289","author":"Phillips","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2021042608273846900_DEV133587C38","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1146\/annurev-genet-120213-092218","article-title":"Cellular and molecular mechanisms of single and collective cell migrations in Drosophila: themes and variations","volume":"48","author":"Pocha","year":"2014","journal-title":"Annu. Rev. Genet."},{"key":"2021042608273846900_DEV133587C39","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/S0092-8674(00)80074-4","article-title":"Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain","volume":"86","author":"Porter","year":"1996","journal-title":"Cell"},{"key":"2021042608273846900_DEV133587C40","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.ydbio.2009.01.042","article-title":"Hedgehog does not guide migrating Drosophila germ cells","volume":"328","author":"Renault","year":"2009","journal-title":"Dev. Biol."},{"key":"2021042608273846900_DEV133587C41","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1126\/science.1166239","article-title":"An ABC transporter controls export of a Drosophila germ cell attractant","volume":"323","author":"Ricardo","year":"2009","journal-title":"Science"},{"key":"2021042608273846900_DEV133587C42","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1146\/annurev.cellbio.042308.113231","article-title":"Collective cell migration","volume":"25","author":"R\u00f8rth","year":"2009","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2021042608273846900_DEV133587C44","doi-asserted-by":"publisher","first-page":"R578","DOI":"10.1016\/j.cub.2004.07.018","article-title":"Germ cell specification and migration in Drosophila and beyond","volume":"14","author":"Santos","year":"2004","journal-title":"Curr. Biol."},{"key":"2021042608273846900_DEV133587C43","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/S1534-5807(04)00023-1","article-title":"Isoprenoids control germ cell migration downstream of HMGCoA reductase","volume":"6","author":"Santos","year":"2004","journal-title":"Dev. Cell"},{"key":"2021042608273846900_DEV133587C45","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.tibs.2014.08.008","article-title":"The UPS and downs of cholesterol homeostasis","volume":"39","author":"Sharpe","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"2021042608273846900_DEV133587C46","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/0092-8674(92)90318-7","article-title":"Overexpression of Oskar directs ectopic activation of nanos and presumptive pole cell formation in Drosophila embryos","volume":"70","author":"Smith","year":"1992","journal-title":"Cell"},{"key":"2021042608273846900_DEV133587C47","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1242\/dev.124.11.2143","article-title":"Hedgehog organises the pattern and polarity of epidermal cells in the Drosophila abdomen","volume":"124","author":"Struhl","year":"1997","journal-title":"Development"},{"key":"2021042608273846900_DEV133587C48","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/0092-8674(94)90175-9","article-title":"Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs","volume":"76","author":"Tabata","year":"1994","journal-title":"Cell"},{"key":"2021042608273846900_DEV133587C49","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1006\/bbrc.1999.1996","article-title":"Overexpression of MDR1 in an intestinal cell line results in increased cholesterol uptake from micelles","volume":"267","author":"Tessner","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021042608273846900_DEV133587C50","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1038\/24871","article-title":"HMG-CoA reductase guides migrating primordial germ cells","volume":"396","author":"Van Doren","year":"1998","journal-title":"Nature"},{"key":"2021042608273846900_DEV133587C51","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.cmet.2007.01.011","article-title":"Drosophila NPC1b promotes an early step in sterol absorption from the midgut epithelium","volume":"5","author":"Voght","year":"2007","journal-title":"Cell Metab."},{"key":"2021042608273846900_DEV133587C52","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1016\/j.bbalip.2015.04.002","article-title":"As the fat flies: The dynamic lipid droplets of Drosophila embryos","volume":"1851","author":"Welte","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"2021042608273846900_DEV133587C53","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.neuron.2009.03.022","article-title":"Sonic hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway","volume":"62","author":"Yam","year":"2009","journal-title":"Neuron"},{"key":"2021042608273846900_DEV133587C54","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1126\/science.1127704","article-title":"The mevalonate pathway controls heart formation in Drosophila by isoprenylation of G\u03b31","volume":"313","author":"Yi","year":"2006","journal-title":"Science"},{"key":"2021042608273846900_DEV133587C55","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.ejcb.2009.11.012","article-title":"Cellular analysis of newly identified Hox downstream genes in Drosophila","volume":"89","author":"Zhai","year":"2010","journal-title":"Eur. J. Cell Biol."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.133587","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/143\/12\/2111\/1842485\/dev133587.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.133587\/2052454\/dev_133587v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.133587\/2052454\/dev_133587v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T01:30:40Z","timestamp":1655602240000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.133587\/264099\/Functioning-of-an-ABC-transporter-Mdr49-in-Hh"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":54,"URL":"https:\/\/doi.org\/10.1242\/dev.133587","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2016,1,1]]},"article-number":"dev.133587"}}