Using mouse and zebrafish models to understand the etiology of developmental defects in Cornelia de Lange Syndrome.
Cornelia de Lange Syndrome (CdLS) is a multisystem birth defects disorder that affects every tissue and organ system in the body. Understanding the factors that contribute to the origins, prevalence, and severity of these developmental defects provides the most direct approach for developing screens and potential treatments for individuals with CdLS. Since the majority of cases of CdLS are caused by haploinsufficiency for NIPBL (Nipped-B-like, which encodes a cohesin-associated protein), we have developed mouse and zebrafish models of CdLS by using molecular genetic tools to create Nipbl-deficient mice and zebrafish (Nipbl(+/-) mice, zebrafish nipbl morphants). Studies of these vertebrate animal models have yielded novel insights into the developmental etiology and genes/gene pathways that contribute to CdLS-associated birth defects, particularly defects of the gut, heart, craniofacial structures, nervous system, and limbs. Studies of these mouse and zebrafish CdLS models have helped clarify how deficiency for NIPBL, a protein that associates with cohesin and other transcriptional regulators in the nucleus, affects processes important to the emergence of the structural and physiological birth defects observed in CdLS: NIPBL exerts chromosome position-specific effects on gene expression; it influences long-range interactions between different regulatory elements of genes; and it regulates combinatorial and synergistic actions of genes in developing tissues. Our current understanding is that CdLS should be considered as not only a cohesinopathy, but also a "transcriptomopathy," that is, a disease whose underlying etiology is the global dysregulation of gene expression throughout the organism. © 2016 Wiley Periodicals, Inc.
Shimako
S
Kawauchi
Rosaysela
R
Santos
Akihiko
A
Muto
Martha E
ME
Lopez-Burks
Thomas F
TF
Schilling
Arthur D
AD
Lander
Anne L
AL
Calof
D000818:Animals; D018797:Cell Cycle Proteins; D000013:Congenital Abnormalities / Q000235:genetics; D003635:De Lange Syndrome / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D011506:Proteins / Q000235:genetics; D015027:Zebrafish
D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D011506:Proteins
Hox genes; Nipped-B-like (NIPBL) gene; Protocadherin genes; Shh genes; chromatin conformation