Role of the ABC transporter Mdr49 in Hedgehog signaling and germ cell migration.
Coalescence of the embryonic gonad in Drosophila melanogaster requires directed migration of primordial germ cells (PGCs) towards somatic gonadal precursor cells (SGPs). It was recently proposed that the 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 loss- and gain-of-function strategies, we show that Mdr49 is a component of the Hedgehog (hh) pathway and it potentiates the signaling activity. This function is direct because in Mdr49 mutant embryos the Hh ligand is inappropriately sequestered in the hh-expressing cells. Our data also suggest that the 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.
Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA gdeshpan@princeton.edu offerg@ekmd.huji.ac.il pschedl@princeton.edu.
Girish
G
Deshpande
Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA.
Diane
D
Manry
Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA.
Nicholas
N
Jourjine
Institute of Gene Biology, Russian Academy of Sciences, Moscow 119334, Russia.
Vladic
V
Mogila
Department of Developmental Biology and Cancer Research, IMRIC, The Hebrew University, Jerusalem 91120, Israel.
Henny
H
Mozes
Department of Developmental Biology and Cancer Research, IMRIC, The Hebrew University, Jerusalem 91120, Israel.
Tzofia
T
Bialistoky
Department of Developmental Biology and Cancer Research, IMRIC, The Hebrew University, Jerusalem 91120, Israel gdeshpan@princeton.edu offerg@ekmd.huji.ac.il pschedl@princeton.edu.
Offer
O
Gerlitz
Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA Institute of Gene Biology, Russian Academy of Sciences, Moscow 119334, Russia gdeshpan@princeton.edu offerg@ekmd.huji.ac.il pschedl@princeton.edu.
Paul
P
Schedl
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D002465:Cell Movement; D002784:Cholesterol / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology; D004843:Epistasis, Genetic; D005247:Feeding Behavior; D020440:Gene Duplication; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006720:Homozygote; D008024:Ligands; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction; D014921:Wings, Animal / Q000002:abnormalities / Q000378:metabolism; D015053:Zygote / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D008024:Ligands; C069935:mdr49 protein, Drosophila; C077245:hh protein, Drosophila; D002784:Cholesterol
Cholesterol; Drosophila melanogaster; Gonad coalescence; Hedgehog; Primordial germ cells