Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome

Akihiko Muto,Arthur D Lander,Anne L Calof,Thomas F Schilling,Derek L Stemple

doi:10.1371/journal.pbio.1001181

Akihiko Muto, Arthur D Lander + Show 3 more

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https://doi.org/10.1371/journal.pbio.1001181

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Journal: PLoS Biology	Publication Date: Oct 25, 2011
Citations: 116	License type: CC BY 4.0

Affiliation: University of California, Irvine

Abstract

Author SummaryAlthough best known for its role in chromatid cohesion, cohesin is increasingly seen as a regulator of gene expression. In Cornelia de Lange Syndrome (CdLS), partial deficiency for NIPBL, which encodes a cohesin regulator, is associated with small changes in the expression of many genes (similar effects are seen in Nipbl-deficient mice and flies). Are such changes responsible for pervasive developmental defects in CdLS? To address this, we used morpholino oligonucleotides to quantitatively reduce levels of Nipbl protein and Nipbl target genes in zebrafish embryos. Combined knockdown of both zebrafish nipbl genes produced heart and gut defects with similarities to those observed in CdLS. Nipbl-deficient embryos showed quantitative changes in the expression of several genes involved in the specification of endoderm, which both gives rise to gut and provides a substrate for cardiac precursor migration, as well as genes that regulate left-right asymmetry. Functional studies of these putative targets suggest that changes in their expression collectively, and in some cases synergistically, contribute to the observed phenotypes. These findings suggest that birth defects in CdLS result from combinatorial, quantitative effects of NIPBL on gene expression, and suggest that cardiac and visceral organ defects in CdLS arise during early embryonic development.

Highlights

Cohesin is a multi-protein complex that associates with the chromosomes of all eukaryotic cells, and mediates sister chromatid cohesion, ensuring appropriate segregation of chromosomes during cell division [1,2]
In Cornelia de Lange Syndrome (CdLS), partial deficiency for NIPBL, which encodes a cohesin regulator, is associated with small changes in the expression of many genes
Are such changes responsible for pervasive developmental defects in CdLS? To address this, we used morpholino oligonucleotides to quantitatively reduce levels of Nipbl protein and Nipbl target genes in zebrafish embryos. Combined knockdown of both zebrafish nipbl genes produced heart and gut defects with similarities to those observed in CdLS

Summary

Introduction

Cohesin is a multi-protein complex that associates with the chromosomes of all eukaryotic cells, and mediates sister chromatid cohesion, ensuring appropriate segregation of chromosomes during cell division [1,2]. Studies on a set of human birth defect syndromes recently termed ‘‘cohesinopathies,’’ along with work in Drosophila and in cell culture, point to roles for cohesin in various processes such as long-range promoter/ enhancer communication, insulator action, and gene activation in the presence of polycomb silencing activity (reviewed by [1]). Many of these studies have focused on a protein known variously as Scc (in yeast and Xenopus), Nipped-B (in Drosophila), or Nipped-B-like (Nipbl, in most vertebrates), which is not itself a cohesin subunit, but is required for the loading of cohesin onto. Clinical data suggest that a mere 15% decrease in NIPBL levels produces a recognizable phenotype [22]

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