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: Grazia Fazio, Carles Gaston-Massuet, Laura Rachele Bettini, Federica Graziola, Valeria Scagliotti, Anna Cereda, Luca Ferrari, Mara Mazzola, Gianni Cazzaniga, Antonio Giordano, Franco Cotelli, Gianfranco Bellipanni, Andrea Biondi, Angelo Selicorni, Anna Pistocchi, Valentina Massa
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 231 Issue 3 Pg. 613-22 (Mar 2016) ISSN: 1097-4652 [Electronic] United States
• PMID: 26206533 (Publication Type: Journal Article)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Ccnd1 protein, mouse
• Cell Cycle Proteins
• Chromosomal Proteins, Non-Histone
• Nipbl protein, mouse
• Smc1l1 protein, mouse
• Transcription Factors
• Zebrafish Proteins
• nipblb protein, zebrafish
• Cyclin D1

Topics

• Animals
• Apoptosis (genetics, physiology)
• Cell Cycle Proteins (genetics, metabolism)
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• Cyclin D1 (metabolism)
• De Lange Syndrome (genetics, metabolism)
• Down-Regulation
• Humans
• Mice
• Mutation (genetics)
• Transcription Factors (genetics, metabolism)
• Zebrafish (embryology, metabolism)
• Zebrafish Proteins (genetics, metabolism)