ETS1 loss in mice impairs cardiac outflow tract septation via a cell migration defect autonomous to the neural crest

Abstract

Ets1 deletion in some mouse strains causes septal defects and has been implicated in human congenital heart defects in Jacobsen syndrome, in which one copy of the Ets1 gene is missing. Here, we demonstrate that loss of Ets1 in mice results in a decrease in neural crest cells migrating into the proximal outflow tract cushions during early heart development, with subsequent malalignment of the cushions relative to the muscular ventricular septum, resembling double outlet right ventricle (DORV) defects in humans. Consistent with this, we find that cultured cardiac neural crest cells from Ets1 mutant mice or derived from iPS cells from Jacobsen patients exhibit decreased migration speed and impaired cell-to-cell interactions. Together, our studies demonstrate a critical role for ETS1 for cell migration in cardiac neural crest cells that are required for proper formation of the proximal outflow tracts. These data provide further insights into the molecular and cellular basis for development of the outflow tracts, and how perturbation of neural crest cells can lead to DORV.

ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3

“…ETS1 is a critical regulator of normal embryonic development (48,49) (60,63). In chick embryos, studies have also defined ETS1's contributions to the gene regulatory network that defines migratory cranial neural crest cells, which give rise to cartilage and bone, regulating the expression of at least four markers of this cell type, RXRG, LTK, COL9A3, LMO4 (62).…”

“…ETS1 is a critical regulator of normal embryonic development (48,49) that exhibits an entirely different expression pattern in adult tissues when it becomes restricted to immune cell sub-types, including B cells, T cells, and NK cells (50)(51)(52)(53). In the developing embryo, ETS1 contributes to the regulation of the mobility and invasive properties of several progenitor cell types, including endothelial cells that contribute to angiogenesis (54)(55)(56) and the diverse cell types that arise from neural crest cells (57)(58)(59)(60)(61)(62)(63). Interestingly, neural crest cells are one of the few cell-types that tolerate EWSR1::FLI1 expression (64).…”

“…Interestingly, neural crest cells are one of the few cell-types that tolerate EWSR1::FLI1 expression (64). Studies of mice, chick, and Xenopus embryos have noted Ets1 expression in pre-migratory and migrating neural crest and neural crest-derived cells, including cardiac and cranial neural crest cells (59)(60)(61)(62)(63). The expression of Ets1 in cardiac neural crest cells appears particularly important as analysis of Ets1 -/mice on some genetic backgrounds demonstrate nearly complete perinatal lethality due to the failure of cardiac neural crest cells to migrate appropriately, resulting in heart malformation (60,63).…”

“…Studies of mice, chick, and Xenopus embryos have noted Ets1 expression in pre-migratory and migrating neural crest and neural crest-derived cells, including cardiac and cranial neural crest cells (59)(60)(61)(62)(63). The expression of Ets1 in cardiac neural crest cells appears particularly important as analysis of Ets1 -/mice on some genetic backgrounds demonstrate nearly complete perinatal lethality due to the failure of cardiac neural crest cells to migrate appropriately, resulting in heart malformation (60,63). In chick embryos, studies have also defined ETS1's contributions to the gene regulatory network that defines migratory cranial neural crest cells, which give rise to cartilage and bone, regulating the expression of at least four markers of this cell type, RXRG, LTK, COL9A3, LMO4 (62).…”

Use of Frogs as a Model to Study the Etiology of HLHS

“…The deletion of the Ets1 locus is the genetic cause for Jacobsen syndrome, in which HLHS is over-represented [ 89 , 90 ]. However, Ets1 KO in mice results in ventricular septal defects, double outlet right ventricle, or ventricular non-compaction, depending on the tissue where Ets1 is deleted, but not HLHS [ 91 , 92 , 93 ]. We have examined the role of Ets1 in frog heart development.…”