Evidence that deletion of ETS-1, a gene in the Jacobsen syndrome (11q-) cardiac critical region, causes congenital heart defects through impaired cardiac neural crest cell function

Abstract

Jacobsen syndrome (11q-) is a rare chromosomal disorder characterized by multiple problems including congenital heart defects, behavioral problems, intellectual disability, dysmorphic features, and bleeding problems. Septal defects, including double outlet right ventricle (DORV), are among the most common CHDs that occur in 11q-. One possible mechanism underlying the CHDs and other problems in 11q- is a defect in neural crest cell function. The E26 avian leukemia 1, 5' domain (ETS-1) gene is a member of the ETS-domain transcription factor family. ETS-1 is deleted in every 11q- patient with CHDs, and gene-targeted deletion of the ETS-1 gene in C57/B6 mice causes DORV with 100 % penetrance. Normal murine cardiac development requires precisely regulated specification of the cardiac neural crest cells (cNCCs). To begin to define the role of ETS-1 in mammalian cardiac development, we have demonstrated that ETS-1 is strongly expressed in mouse cNCCs during early heart development. Sox10 is a key regulator for the neural crest cell gene regulatory network. It is also an early marker for NCCs, and its expression can facilitate the analysis of cNCC function during embryonic development. We have demonstrated that loss of ETS-1 causes decreased migrating Sox10- expressing cells in E10.5 C57/B6 mouse embryos. These results suggest a NCC migration defect in ETS-1 mutants. Our data support the hypothesis that ETS-1 is required for specification and migration of cNCCs and for regulating a cNCC-specific gene regulatory network that is required for normal cardiac development.