Gastrulation-stage gene expression in <i>Nipbl</i>^+/- mouse embryos foreshadows the development of syndromic birth defects.

Abstract

In animal models, <i>Nipbl</i> deficiency phenocopies gene expression changes and birth defects seen in Cornelia de Lange syndrome, the most common cause of which is <i>Nipbl</i> haploinsufficiency. Previous studies in <i>Nipbl^+/-</i> mice suggested that heart development is abnormal as soon as cardiogenic tissue is formed. To investigate this, we performed single-cell RNA sequencing on wild-type and <i>Nipbl^+/-</i> mouse embryos at gastrulation and early cardiac crescent stages. <i>Nipbl^+/-</i> embryos had fewer mesoderm cells than wild-type and altered proportions of mesodermal cell subpopulations. These findings were associated with underexpression of genes implicated in driving specific mesodermal lineages. In addition, <i>Nanog</i> was found to be overexpressed in all germ layers, and many gene expression changes observed in <i>Nipbl^+/-</i> embryos could be attributed to <i>Nanog</i> overexpression. These findings establish a link between <i>Nipbl</i> deficiency, <i>Nanog</i> overexpression, and gene expression dysregulation/lineage misallocation, which ultimately manifest as birth defects in <i>Nipbl^+/-</i> animals and Cornelia de Lange syndrome.