title: Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior.
abstract: Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects.
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Gause
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dongbin
authors.initials: D
authors.lastname: Xu
authors.affiliation: Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Ziva
authors.initials: Z
authors.lastname: Misulovin
authors.affiliation: Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Cheri A
authors.initials: CA
authors.lastname: Schaaf
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ramya C
authors.initials: RC
authors.lastname: Mosarla
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mannino
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Shannon
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Jones
authors.affiliation: Howard Hughes Medical Institute and Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mi
authors.initials: M
authors.lastname: Shi
authors.affiliation: Howard Hughes Medical Institute and Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Chen
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Katz
authors.affiliation: Howard Hughes Medical Institute and Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Amita
authors.initials: A
authors.lastname: Sehgal
authors.affiliation: Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jongens
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.|Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.affiliation: Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Dale
authors.initials: D
authors.lastname: Dorsett
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D003635:De Lange Syndrome / Q000235:genetics*; D004330:Drosophila / Q000235:genetics / Q000254:growth & development* / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics*; D006579:Heterozygote; D008954:Models, Biological; D009154:Mutation
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C119839:nipped-B protein, Drosophila