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

Abstract

In animal models, Nipbl-deficiency phenocopies gene expression changes and birth defects seen in Cornelia de Lange Syndrome (CdLS), the most common cause of which is Nipbl-haploinsufficiency. Previous studies in Nipbl+/- 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) and Nipbl+/- 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 in Nipbl+/- mice, offering insights into early developmental contributions to birth defects in CdLS.

Cohesin composition and dosage independently affect early development in zebrafish

“…It is possible that some of the molecular basis for developmental abnormalities is shared between NIPBL deficiency and STAG2 mutation. A study describing single cell RNA sequencing of early-stage mouse embryos with one deleted copy of Nipbl showed that these embryos also experience changes in mesoderm fate and have altered mesoderm cell populations (Chea et al, 2024). Nipbl loss altered the regulation of genes involved in EMT, which parallels our findings in stag2b mutant zebrafish embryos.…”