Santos Rosaysela, Kawauchi Shimako, Jacobs Russell E, Lopez-Burks Martha E, Choi Hojae, Wikenheiser Jamie, Hallgrimsson Benedikt, Jamniczky Heather A, Fraser Scott E, Lander Arthur D, Calof Anne L
Department of Developmental and Cell Biology, University of California, Irvine, California, United States of America.
Center for Complex Biological Systems, University of California, Irvine, California, United States of America.
PLoS Biol. 2016 Sep 8;14(9):e2000197. doi: 10.1371/journal.pbio.2000197. eCollection 2016 Sep.
Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form.
哺乳动物心脏复杂的形态发生过程使得阐明先天性心脏缺陷的病因变得困难。心脏形态发生在发育早期进行，涉及多个胚层的参与，并受许多基因控制。在这里，我们使用一种条件性/可逆性遗传策略，在科妮莉亚·德朗热综合征的Nipbl缺陷小鼠模型中确定导致心脏缺陷的细胞谱系。在该模型中，整体但微妙的转录失调导致高频发生房间隔缺损（ASD）。通过一种允许在不同谱系中通过重组酶介导产生或挽救Nipbl缺陷的方法，我们揭示了心脏中胚层、内胚层与胚胎其他部分之间的复杂相互作用，即任何一个谱系中的基因异常所带来的风险会以一种惊人的非累加方式，被其他谱系的状态所改变。我们认为，在一个模型背景下能最好地理解这些结果，该模型中，心脏缺陷的风险与早期祖细胞群体相对于它们最终必须形成的结构大小的充足程度相关。
