Cornelia de Lange Syndrome (CdLS) is a multi-organ system constellation of birth defects caused by dysfunction of cohesin, a protein complex required for chromosome cohesion, and recently implicated in the regulation of gene expression. This work will continue the development and analysis of two animal models of A//pib/-deficiency, the most common genetic cause of CdLS. The Nipbl+I- mouse replicates many features of CdLS including a high frequency of cardiac septal abnormalities. The A//pW-morphant zebrafish also displays cardiac defects, as well as gut defects that are typical of CdLS. In both systems, Nipbl deficiency appears to cause hundreds of relatively small, often tissue-specific, changes in gene expression, just as has been seen in cell lines from individuals with CdLS. The goal of the proposed work is to exploit the mouse and fish models to (1) understand the origins of heart defects in CdLS, and (2) determine the extent to which major structural defects in CdLS have a combinatorial etiology-i.e. arise as the result of synergistic interactions among small changes in the expression of multiple genes.
The first aim will be accomplished using newly-developed transgenic mouse lines that harbor conditional/invertible (FLEx) alleles of Nipbl, which may be successively toggled from functionally-mutant to wildtype, and back again to mutant. Using these mouse lines, the timing and cell type(s) of origin of cardiac septal defects will be pinpointed, and potentially causal changes in gene expression identified.
The second aim will be accomplished using a zebrafish model of CdLS. Experiments in this aim will focus on the identification of new potential Nipbl """"""""target"""""""" genes, and the quantitative manipulation of their expression during early embryogenesis. Accomplishing these aims should not only aid in understanding, treating and/or preventing birth defects in CdLS;it is also likely to provide novel insights into the origins of non-syndromic birth defects, which are much more common, but may also frequently result from combinatorial interactions among small-effect alleles in the general population.
The impact of structural birth defects on human health is enormous. Animal models of Cornelia de Lange Syndrome (CdLS) will be exploited to generate new insights into the origins of birth defects, especially those of the heart and gut. Because of the way the gene defect underlying this syndrome works, there is a good probability that the results obtained will be directly relevant to common causes of birth defects in the general population.
|Yuen, Kobe C; Xu, Baoshan; Krantz, Ian D et al. (2016) NIPBL Controls RNA Biogenesis to Prevent Activation of the Stress Kinase PKR. Cell Rep 14:93-102|
|Lopez-Burks, Martha E; Santos, Rosaysela; Kawauchi, Shimako et al. (2016) Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome. Am J Med Genet C Semin Med Genet 172:146-54|
|Kawauchi, Shimako; Santos, Rosaysela; Muto, Akihiko et al. (2016) Using mouse and zebrafish models to understand the etiology of developmental defects in Cornelia de Lange Syndrome. Am J Med Genet C Semin Med Genet 172:138-45|
|Santos, Rosaysela; Kawauchi, Shimako; Jacobs, Russell E et al. (2016) Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. PLoS Biol 14:e2000197|
|Dorsett, Dale (2016) The Drosophila melanogaster model for Cornelia de Lange syndrome: Implications for etiology and therapeutics. Am J Med Genet C Semin Med Genet 172:129-37|
|Wu, Yaning; Gause, Maria; Xu, Dongbin et al. (2015) Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior. PLoS Genet 11:e1005655|
|Ramos, Feliciano J; Puisac, Beatriz; Baquero-Montoya, Carolina et al. (2015) Clinical utility gene card for: Cornelia de Lange syndrome. Eur J Hum Genet 23:|
|Izumi, Kosuke; Nakato, Ryuichiro; Zhang, Zhe et al. (2015) Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet 47:338-44|
|Krantz, Ian D (2014) Cohesin embraces new phenotypes. Nat Genet 46:1157-8|
|Visnes, T; Giordano, F; Kuznetsova, A et al. (2014) Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I. Chromosoma 123:239-52|
Showing the most recent 10 out of 66 publications