title: Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome.
abstract: Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75-80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only approximately 30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/- mice and in individuals with CdLS.
authors.affiliation: Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Shimako
authors.initials: S
authors.lastname: Kawauchi
authors.forename: Anne L
authors.initials: AL
authors.lastname: Calof
authors.forename: Rosaysela
authors.initials: R
authors.lastname: Santos
authors.forename: Martha E
authors.initials: ME
authors.lastname: Lopez-Burks
authors.forename: Clint M
authors.initials: CM
authors.lastname: Young
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Hoang
authors.forename: Abigail
authors.initials: A
authors.lastname: Chua
authors.forename: Taotao
authors.initials: T
authors.lastname: Lao
authors.forename: Mark S
authors.initials: MS
authors.lastname: Lechner
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Leonard
authors.initials: L
authors.lastname: Kitzes
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yokomori
authors.forename: Benedikt
authors.initials: B
authors.lastname: Hallgrimsson
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Lander
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development; D001842:Bone and Bones / Q000002:abnormalities / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D019465:Craniofacial Abnormalities / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003635:De Lange Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006579:Heterozygote; D051379:Mice; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D009928:Organ Specificity / Q000235:genetics*; D010641:Phenotype; D012854:Sister Chromatid Exchange; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D015820:Cadherins; D018797:Cell Cycle Proteins; C546088:Nipbl protein, mouse; D014157:Transcription Factors