Gastrulation-stage gene expression inNipbl+/-mouse embryos foreshadows the development of syndromic birth defects

Abstract

AbstractIn animal models,Nipbl-deficiency phenocopies gene expression changes and birth defects seen in Cornelia de Lange Syndrome (CdLS), the most common cause of which isNipbl-haploinsufficiency. Previous studies inNipbl+/-mice identified aberrant gene expression and heart defects as early as cardiac crescent (CC) stage. Here, we performed single-cell RNA-sequencing on wildtype (WT) andNipbl+/-mouse embryos at CC- and earlier (gastrulation) stages.Nipbl+/-embryos had fewer mesoderm cells than WT and altered proportions of mesodermal cell subpopulations. These findings were associated with an underexpression of genes implicated in driving specific mesodermal lineages.Nipbl+/-embryos also misexpressed developmentally-critical genes, including the transcription factor,Nanog, and genes governing left-right and anterior-posterior patterning. These events of cell misallocation and transcriptional dysregulation foreshadowed defects in tissue composition and patterning that arise later inNipbl+/-mice, offering insights into early developmental contributions to birth defects in CdLS.TeaserGene expression changes during gastrulation ofNipbl-deficient mice shed light on early origins of structural birth defects.