Prdm6 controls heart development by regulating neural crest cell differentiation and migration.

Lingjuan Hong,Anne Eichmann,Yinyu Wu,Caroline Hendry,Karen K Hirschi,Victor Gasque,Arya Mani,Lupeng Ye,Sameet Mehta,Na Li,Jürgen Ruland,Andreas Gewies,David Van Dijk,Jinyu Li

doi:10.1172/jci.insight.156046

Abstract

The molecular mechanisms that drive the acquisition of distinct neural crest cell (NCC) fates is still poorly understood. Here, we identified Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating cardiac NCCs (CNCCs). Using transcriptomic analysis and genetic and fate mapping approaches in transgenic mice, we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction. Bulk and single-cell RNA-Seq analyses of the DA and CNCCs identified Prdm6 as a regulator of a network of CNCC specification genes, including Wnt1, Tfap2b, and Sox9. Loss of Prdm6 in CNCCs diminished its expression in the pre-epithelial–mesenchymal transition (pre-EMT) cluster, resulting in the retention of NCCs in the dorsal neural tube. This defect was associated with diminished H4K20 monomethylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we showed was the major driver of the impaired CNCC migration. Altogether, these findings revealed Prdm6 as a key regulator of CNCC differentiation and migration and identified Prdm6 and its regulated network as potential targets for the treatment of congenital heart diseases.

Highlights

Neural crest cells (NCCs) are a transient population of multipotent cells unique to vertebrates that arise from neural folds during embryonic development [1] and migrate throughout the body, giving rise to diverse cell lineages
According to an earlier study, Wnt1 expression in cardiac NCCs (CNCCs) starts on dpc 8–8.5 [15], while Prdm6 expression has been shown to be readily detectable in the embryo by E9.5 using Northern blot analysis [8]
The examination of the heart showed biventricular noncompaction but no other structural defect (Figure 1E). These findings indicate that Prdm6 expression in CNCCs is required for proper closure of the ductus arteriosus (DA) and the development of compacted myocardium during embryonic development

Summary

Introduction

Neural crest cells (NCCs) are a transient population of multipotent cells unique to vertebrates that arise from neural folds during embryonic development [1] and migrate throughout the body, giving rise to diverse cell lineages. Cardiac NCCs (CNCCs) — precursors to the heart — are generated at 8–8.5 dpc and arrive in the distal outflow at E9–9.5 [2]. Targeted ablation of Wnt1-expressing CNCCs at 8.5 dpc in mice results in a complex phenotype of craniofacial and cardiovascular outflow tract defects [3]. The impaired function of CNCCs in humans underlies the pathogenesis of various complex human congenital disorders collectively known as cardio craniofacial syndromes [4]. The mechanisms underlying the pleiotropic effects of CNCCs are not understood owing to a lack of insight into how subsets of CNCCs are specified and how their subsequent fate is determined

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Results

Conclusion