title: CyclinD1 Down-Regulation and Increased Apoptosis Are Common Features of Cohesinopathies.
abstract: Genetic variants within components of the cohesin complex (NIPBL, SMC1A, SMC3, RAD21, PDS5, ESCO2, HDAC8) are believed to be responsible for a spectrum of human syndromes known as "cohesinopathies" that includes Cornelia de Lange Syndrome (CdLS). CdLS is a multiple malformation syndrome affecting almost any organ and causing severe developmental delay. Cohesinopathies seem to be caused by dysregulation of specific developmental pathways downstream of mutations in cohesin components. However, it is still unclear how mutations in different components of the cohesin complex affect the output of gene regulation. In this study, zebrafish embryos and SMC1A-mutated patient-derived fibroblasts were used to analyze abnormalities induced by SMC1A loss of function. We show that the knockdown of smc1a in zebrafish impairs neural development, increases apoptosis, and specifically down-regulates Ccnd1 levels. The same down-regulation of cohesin targets is observed in SMC1A-mutated patient fibroblasts. Previously, we have demonstrated that haploinsufficiency of NIPBL produces similar effects in zebrafish and in patients fibroblasts indicating a possible common feature for neurological defects and mental retardation in cohesinopathies. Interestingly, expression analysis of Smc1a and Nipbl in developing mouse embryos reveals a specific pattern in the hindbrain, suggesting a role for cohesins in neural development in vertebrates.
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Fazio
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary University of London, London, UK.
authors.forename: Carles
authors.initials: C
authors.lastname: Gaston-Massuet
authors.affiliation: Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.
authors.forename: Laura Rachele
authors.initials: LR
authors.lastname: Bettini
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary University of London, London, UK.|Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Graziola
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary University of London, London, UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Scagliotti
authors.affiliation: Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cereda
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ferrari
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Mazzola
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.|Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cotelli
authors.affiliation: Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.|Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Bellipanni
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.|Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.|Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pistocchi
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Massa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D003635:De Lange Syndrome / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D019938:Cyclin D1; D014157:Transcription Factors; D029961:Zebrafish Proteins; C530105:Ccnd1 protein, mouse; C546088:Nipbl protein, mouse; C120423:Smc1l1 protein, mouse; C570219:nipblb protein, zebrafish; D000097722:Cohesins