Drosophila homolog of the intellectual disability-related long-chain acyl-CoA synthetase 4 is required for neuroblast proliferation
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摘要
Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic X-linked intellectual disability (ID). However, the neural functions of ACSL4 and how loss of ACSL4 leads to ID remain largely unexplored. We report here that mutations in Acsl, the Drosophila ortholog of human ACSL3 and ACSL4, result in developmental defects of the mushroom body (MB), the center of olfactory learning and memory. Specifically, Acsl mutants show fewer MB neuroblasts (Nbs) due to reduced proliferation activity and premature differentiation. Consistently, these surviving Nbs show reduced expression of cyclin E, a key regulator of the G1-to S-phase cell cycle transition, and nuclear mislocalization of the transcriptional factor Prospero, which is known to repress self-renewal genes and activate differentiating genes. Furthermore, RNA-seq analysis reveals downregulated Nb-and cell-cyclerelated genes and upregulated neuronal differentiation genes in Acsl mutant Nbs. As Drosophila Acsl and human ACSL4 are functionally conserved, our findings provide novel insights into a critical and previously unappreciated role of Acsl in neurogenesis and the pathogenesis of ACSL4-related ID.
Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic X-linked intellectual disability (ID). However, the neural functions of ACSL4 and how loss of ACSL4 leads to ID remain largely unexplored. We report here that mutations in Acsl, the Drosophila ortholog of human ACSL3 and ACSL4, result in developmental defects of the mushroom body (MB), the center of olfactory learning and memory. Specifically, Acsl mutants show fewer MB neuroblasts (Nbs) due to reduced proliferation activity and premature differentiation. Consistently, these surviving Nbs show reduced expression of cyclin E, a key regulator of the G1-to S-phase cell cycle transition, and nuclear mislocalization of the transcriptional factor Prospero, which is known to repress self-renewal genes and activate differentiating genes. Furthermore, RNA-seq analysis reveals downregulated Nb-and cell-cyclerelated genes and upregulated neuronal differentiation genes in Acsl mutant Nbs. As Drosophila Acsl and human ACSL4 are functionally conserved, our findings provide novel insights into a critical and previously unappreciated role of Acsl in neurogenesis and the pathogenesis of ACSL4-related ID.
Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic X-linked intellectual disability (ID). However, the neural functions of ACSL4 and how loss of ACSL4 leads to ID remain largely unexplored. We report here that mutations in Acsl, the Drosophila ortholog of human ACSL3 and ACSL4, result in developmental defects of the mushroom body (MB), the center of olfactory learning and memory. Specifically, Acsl mutants show fewer MB neuroblasts (Nbs) due to reduced proliferation activity and premature differentiation. Consistently, these surviving Nbs show reduced expression of cyclin E, a key regulator of the G1-to S-phase cell cycle transition, and nuclear mislocalization of the transcriptional factor Prospero, which is known to repress self-renewal genes and activate differentiating genes. Furthermore, RNA-seq analysis reveals downregulated Nb-and cell-cyclerelated genes and upregulated neuronal differentiation genes in Acsl mutant Nbs. As Drosophila Acsl and human ACSL4 are functionally conserved, our findings provide novel insights into a critical and previously unappreciated role of Acsl in neurogenesis and the pathogenesis of ACSL4-related ID.
引文
An,H.,Ge,W.,Xi,Y.,Yang,X.,2017.Inscuteable maintains type I neuroblast lineage identity via Numb/Notch signaling in the Drosophila larval brain.J.Genet.Genomics 44,151e162.
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Berger,C.,Harzer,H.,Burkard,T.R.,Steinmann,J.,van der Horst,S.,Laurenson,A.S.,Novatchkova,M.,Reichert,H.,Knoblich,J.A.,2012.FACS purification and transcriptome analysis of Drosophila neural stem cells reveals a role for Klumpfuss in self-renewal.Cell Rep.2,407e418.
Bowman,S.K.,Rolland,V.,Betschinger,J.,Kinsey,K.A.,Emery,G.,Knoblich,J.A.,2008.The tumor suppressors brat and numb regulate transit-amplifying neuroblast lineages in Drosophila.Dev.Cell 14,535e546.
Cabernard,C.,Doe,C.Q.,2009.Apical/Basal spindle orientation is required for neuroblast homeostasis and neuronal differentiation in Drosophila.Dev.Cell 17,134e141.
Cabernard,C.,Doe,C.Q.,2013.Live imaging of neuroblast lineages within intact larval brains in Drosophila.Cold Spring Harb.Protoc.2013,970e977.
Cao,Y.,Murphy,K.J.,McIntyre,T.M.,Zimmerman,G.A.,Prescott,S.M.,2000.Expression of fatty acid-CoA ligase 4 during development and in brain.FEBSLett.467,263e267.
Cenci,C.,Gould,A.P.,2005.Drosophila Grainyhead specifies late programmes of neural proliferation by regulating the mitotic activity and Hox-dependent apoptosis of neuroblasts.Development 132,3835e3845.
Ceron,J.,Tejedor,F.J.,Moya,F.,2006.A primary cell culture of Drosophila postembryonic larval neuroblasts to study cell cycle and asymmetric division.Eur.J.Cell Biol.85,567e575.
Cheng,L.Y.,Bailey,A.P.,Leevers,S.J.,Ragan,T.J.,Driscoll,P.C.,Gould,A.P.,2011.Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila.Cell 146,435e447.
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Harzer,H.,Berger,C.,Conder,R.,Schmauss,G.,Knoblich,J.A.,2013.FACS purification of Drosophila larval neuroblasts for next-generation sequencing.Nat.Protoc.8,1088e1099.
Heisenberg,M.,2003.Mushroom body memoir:from maps to models.Nat.Rev.Neurosci.4,266e275.
Hirata,J.,Nakagoshi,H.,Nabeshima,Y.,Matsuzaki,F.,1995.Asymmetric segregation of the homeodomain protein Prospero during Drosophila development.Nature377,627e630.
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Ihaka,R.,Gentleman,R.,1996.R:a language for data analysis and graphics.J.Comput.Graph Stat.5,299e314.
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Ito,K.,Awano,W.,Suzuki,K.,Hiromi,Y.,Yamamoto,D.,1997.The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells.Development 124,761e771.
Kim,D.,Langmead,B.,Salzberg,S.L.,2015.HISAT:a fast spliced aligner with low memory requirements.Nat.Methods 12,357e360.
Knoblich,J.A.,Jan,L.Y.,Jan,Y.N.,1995.Asymmetric segregation of numb and Prospero during cell-division.Nature 377,624e627.
Knobloch,M.,Braun,S.M.G.,Zurkirchen,L.,von Schoultz,C.,Zamboni,N.,ArauzoBravo,M.J.,Kovacs,W.J.,Karalay,O.,Suter,U.,Machado,R.A.C.,Roccio,M.,Lutolf,M.P.,Semenkovich,C.F.,Jessberger,S.,2013.Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis.Nature 493,226e230.
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Lai,S.L.,Doe,C.Q.,2014.Transient nuclear Prospero induces neural progenitor quiescence.e Life 3,e03363.
Lai,S.L.,Miller,M.R.,Robinson,K.J.,Doe,C.Q.,2012.The Snail family member Worniu Is continuously required in neuroblasts to prevent Elav-induced premature differentiation.Dev.Cell 23,849e857.
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Liu,Z.H.,Huang,Y.,Hu,W.,Huang,S.,Wang,Q.F.,Han,J.H.,Zhang,Y.Q.,2014.d Acsl,the Drosophila ortholog of Acyl-CoA synthetase long-chain family member 3and 4,inhibits synapse growth by attenuating bone morphogenetic protein signaling via endocytic recycling.J.Neurosci.34,2785e2796.
Longo,I.,Frints,S.G.M.,Fryns,J.P.,Meloni,I.,Pescucci,C.,Ariani,F.,Borghgraef,M.,Raynaud,M.,Marynen,P.,Schwartz,C.,Renieri,A.,Froyen,G.,2003.A third MRXfamily(MRX68)is the result of mutation in the long chain fatty acid-CoA ligase4(FACL4)gene:proposal of a rapid enzymatic assay for screening mentally retarded patients.J.Med.Genet.40,11e17.
Lu,B.,Rothenberg,M.,Jan,L.Y.,Jan,Y.N.,1998.Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors.Cell 95,225e235.
Maurange,C.,Cheng,L.,Gould,A.P.,2008.Temporal transcription factors and their targets schedule the end of neural proliferation in Drosophila.Cell 133,891e902.
Meloni,I.,Parri,V.,De Filippis,R.,Ariani,F.,Artuso,R.,Bruttini,M.,Katzaki,E.,Longo,I.,Mari,F.,Bellan,C.,Dotti,C.G.,Renieri,A.,2009.The Xlmr gene Acsl4plays a role in dendritic spine architecture.Neuroscience 159,657e669.
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Cabernard,C.,Doe,C.Q.,2009.Apical/Basal spindle orientation is required for neuroblast homeostasis and neuronal differentiation in Drosophila.Dev.Cell 17,134e141.
Cabernard,C.,Doe,C.Q.,2013.Live imaging of neuroblast lineages within intact larval brains in Drosophila.Cold Spring Harb.Protoc.2013,970e977.
Cao,Y.,Murphy,K.J.,McIntyre,T.M.,Zimmerman,G.A.,Prescott,S.M.,2000.Expression of fatty acid-CoA ligase 4 during development and in brain.FEBSLett.467,263e267.
Cenci,C.,Gould,A.P.,2005.Drosophila Grainyhead specifies late programmes of neural proliferation by regulating the mitotic activity and Hox-dependent apoptosis of neuroblasts.Development 132,3835e3845.
Ceron,J.,Tejedor,F.J.,Moya,F.,2006.A primary cell culture of Drosophila postembryonic larval neuroblasts to study cell cycle and asymmetric division.Eur.J.Cell Biol.85,567e575.
Cheng,L.Y.,Bailey,A.P.,Leevers,S.J.,Ragan,T.J.,Driscoll,P.C.,Gould,A.P.,2011.Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila.Cell 146,435e447.
Choksi,S.P.,Southall,T.D.,Bossing,T.,Edoff,K.,de Wit,E.,Fischer,B.E.,van Steensel,B.,Micklem,G.,Brand,A.H.,2006.Prospero acts as a binary switch between self-renewal and differentiation in Drosophila neural stem cells.Dev.Cell 11,775e789.
Crittenden,J.R.,Skoulakis,E.M.C.,Han,K.-A.,Kalderon,D.,Davis,R.L.,1998.Tripartite mushroom body architecture revealed by antigenic markers.Learn.Mem.5,38e51.
Gandhi,R.,Bonaccorsi,S.,Wentworth,D.,Doxsey,S.,Gatti,M.,Pereira,A.,2004.The Drosophila kinesin-like protein KLP67A is essential for mitotic and male meiotic spindle assembly.Mol.Biol.Cell 15,121e131.
Giet,R.,Glover,D.M.,2001.Drosophila aurora B kinase is required for histone H3phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis.J.Cell Biol.152,669e682.
Grevengoed,T.J.,Klett,E.L.,Coleman,R.A.,2014.Acyl-CoA metabolism and partitioning.Annu.Rev.Nutr.34,1e30.
Harzer,H.,Berger,C.,Conder,R.,Schmauss,G.,Knoblich,J.A.,2013.FACS purification of Drosophila larval neuroblasts for next-generation sequencing.Nat.Protoc.8,1088e1099.
Heisenberg,M.,2003.Mushroom body memoir:from maps to models.Nat.Rev.Neurosci.4,266e275.
Hirata,J.,Nakagoshi,H.,Nabeshima,Y.,Matsuzaki,F.,1995.Asymmetric segregation of the homeodomain protein Prospero during Drosophila development.Nature377,627e630.
Homem,C.C.F.,Knoblich,J.A.,2012.Drosophila neuroblasts:a model for stem cell biology.Development 139,4297e4310.
Homem,C.C.F.,Repic,M.,Knoblich,J.A.,2015.Proliferation control in neural stem and progenitor cells.Nat.Rev.Neurosci.16,647e659.
Huang,D.W.,Sherman,B.T.,Lempicki,R.A.,2009.Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.Nat.Protoc.4,44e57.
Huang,Y.,Huang,S.,Lam,S.M.,Liu,Z.,Shui,G.,Zhang,Y.Q.,2016.Acsl,the Drosophila ortholog of intellectual-disability-related ACSL4,inhibits synaptic growth by altered lipids.J.Cell Sci.129,4034e4045.
Ihaka,R.,Gentleman,R.,1996.R:a language for data analysis and graphics.J.Comput.Graph Stat.5,299e314.
Ikeshima-Kataoka,H.,Skeath,J.B.,Nabeshima,Y.,Doe,C.Q.,Matsuzaki,F.,1997.Miranda directs Prospero to a daughter cell during Drosophila asymmetric divisions.Nature 390,625e629.
Ito,K.,Hotta,Y.,1992.Proliferation pattern of postembryonic neuroblasts in the brain of Drosophila melanogaster.Dev.Biol.149,134e148.
Ito,K.,Awano,W.,Suzuki,K.,Hiromi,Y.,Yamamoto,D.,1997.The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells.Development 124,761e771.
Kim,D.,Langmead,B.,Salzberg,S.L.,2015.HISAT:a fast spliced aligner with low memory requirements.Nat.Methods 12,357e360.
Knoblich,J.A.,Jan,L.Y.,Jan,Y.N.,1995.Asymmetric segregation of numb and Prospero during cell-division.Nature 377,624e627.
Knobloch,M.,Braun,S.M.G.,Zurkirchen,L.,von Schoultz,C.,Zamboni,N.,ArauzoBravo,M.J.,Kovacs,W.J.,Karalay,O.,Suter,U.,Machado,R.A.C.,Roccio,M.,Lutolf,M.P.,Semenkovich,C.F.,Jessberger,S.,2013.Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis.Nature 493,226e230.
Kunz,T.,Kraft,K.F.,Technau,G.M.,Urbach,R.,2012.Origin of Drosophila mushroom body neuroblasts and generation of divergent embryonic lineages.Development 139,2510e2522.
Lai,S.L.,Doe,C.Q.,2014.Transient nuclear Prospero induces neural progenitor quiescence.e Life 3,e03363.
Lai,S.L.,Miller,M.R.,Robinson,K.J.,Doe,C.Q.,2012.The Snail family member Worniu Is continuously required in neuroblasts to prevent Elav-induced premature differentiation.Dev.Cell 23,849e857.
Lee,L.A.,Orr-Weaver,T.L.,2003.Regulation of cell cycles in Drosophila development:intrinsic and extrinsic cues.Annu.Rev.Genet.37,545e578.
Lee,T.,Luo,L.Q.,1999.Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis.Neuron 22,451e461.
Lee,T.,Lee,A.,Luo,L.Q.,1999.Development of the Drosophila mushroom bodies:sequential generation of three distinct types of neurons from a neuroblast.Development 126,4065e4076.
Liu,Z.H.,Huang,Y.,Zhang,Y.,Chen,D.,Zhang,Y.Q.,2011.Drosophila Acyl-CoAsynthetase long-chain family member 4 regulates axonal transport of synaptic vesicles and is required for synaptic development and transmission.J.Neurosci.31,2052e2063.
Liu,Z.H.,Huang,Y.,Hu,W.,Huang,S.,Wang,Q.F.,Han,J.H.,Zhang,Y.Q.,2014.d Acsl,the Drosophila ortholog of Acyl-CoA synthetase long-chain family member 3and 4,inhibits synapse growth by attenuating bone morphogenetic protein signaling via endocytic recycling.J.Neurosci.34,2785e2796.
Longo,I.,Frints,S.G.M.,Fryns,J.P.,Meloni,I.,Pescucci,C.,Ariani,F.,Borghgraef,M.,Raynaud,M.,Marynen,P.,Schwartz,C.,Renieri,A.,Froyen,G.,2003.A third MRXfamily(MRX68)is the result of mutation in the long chain fatty acid-CoA ligase4(FACL4)gene:proposal of a rapid enzymatic assay for screening mentally retarded patients.J.Med.Genet.40,11e17.
Lu,B.,Rothenberg,M.,Jan,L.Y.,Jan,Y.N.,1998.Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors.Cell 95,225e235.
Maurange,C.,Cheng,L.,Gould,A.P.,2008.Temporal transcription factors and their targets schedule the end of neural proliferation in Drosophila.Cell 133,891e902.
Meloni,I.,Parri,V.,De Filippis,R.,Ariani,F.,Artuso,R.,Bruttini,M.,Katzaki,E.,Longo,I.,Mari,F.,Bellan,C.,Dotti,C.G.,Renieri,A.,2009.The Xlmr gene Acsl4plays a role in dendritic spine architecture.Neuroscience 159,657e669.
Meloni,I.,Muscettola,M.,Raynaud,M.,Longo,I.,Bruttini,M.,Moizard,M.P.,Gomot,M.,Chelly,J.,des Portes,V.,Fryns,J.P.,Ropers,H.H.,Magi,B.,Bellan,C.,Volpi,N.,Yntema,H.G.,Lewis,S.E.,Schaffer,J.E.,Renieri,A.,2002.FACL4,encoding fatty acid-CoA ligase 4,is mutated in nonspecific X-linked mental retardation.Nat.Genet.30,436e440.
Melzer,J.,Kraft,K.F.,Urbach,R.,Raabe,T.,2013.The p21-activated kinase Mbt is a component of the apical protein complex in central brain neuroblasts and controls cell proliferation.Development 140,1871e1881.
Ming,G.-l.,Song,H.,2011.Adult neurogenesis in the mammalian brain:significant answers and significant questions.Neuron 70,687e702.
Mitchell,K.J.,Doyle,J.L.,Serafini,T.,Kennedy,T.E.,Tessier-Lavigne,M.,Goodman,C.S.,Dickson,B.J.,1996.Genetic analysis of Netrin genes in Drosophila:netrins guide CNS commissural axons and peripheral motor axons.Neuron 17,203e215.
Pertea,M.,Kim,D.,Pertea,G.M.,Leek,J.T.,Salzberg,S.L.,2016.Transcript-level expression analysis of RNA-seq experiments with HISAT,StringTie and Ballgown.Nat.Protoc.11,1650e1667.
Poon,C.L.,Mitchell,K.A.,Kondo,S.,Cheng,L.Y.,Harvey,K.F.,2016.The Hippo pathway regulates neuroblasts and brain size in Drosophila melanogaster.Curr.Biol.26,1034e1042.
Ropers,H.H.,2008.Genetics of intellectual disability.Curr.Opin.Genet.Dev.18,241e250.
Ropers,H.H.,Hamel,B.C.J.,2005.X-linked mental retardation.Nat.Rev.Genet.6,46e57.
Roth,M.,Roubinet,C.,Ifflander,N.,Ferrand,A.,Cabernard,C.,2015.Asymmetrically dividing Drosophila neuroblasts utilize two spatially and temporally independent cytokinesis pathways.Nat.Commun.6,6551.
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