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.
Highlights
We find that Drosophila with one mutant copy of the Nipped-B gene, which is equivalent to the NIPBL gene, show characteristics similar to individuals with Cornelia de Lange Syndrome (CdLS)
The ring-like cohesin complex consisting of the Smc1, Smc3, Stromalin (SA) and Rad21 proteins is required for sister chromatid cohesion and accurate chromosome segregation
Individuals with CdLS are usually small for their age, but the reasons for their reduced size are largely unknown, and could potentially reflect altered systemic growth control, delayed developmental timing, reduced cell division, reduced utilization of nutrition, increased cell death, or any combination of these factors
Summary
The ring-like cohesin complex consisting of the Smc, Smc, Stromalin (SA) and Rad proteins is required for sister chromatid cohesion and accurate chromosome segregation. Cohesin and releasin function in gene transcription in a dosage-sensitive manner Reductions in their activities alter the expression of hundreds of genes that control growth and development in metazoan organisms. In addition to direct control of active gene transcription, evidence from Drosophila shows that cohesin indirectly controls epigenetic silencing of homeotic genes by Polycomb complexes via sequestration of the PRC1 Polycomb complex at active genes and limiting the amount available for silencing [4]. It is currently unknown if cohesin plays a similar role in mammalian Polycomb silencing
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