MRPL40 Regulates Cardiac Outflow Tract Septation by Modulating Neural Crest Cell Migration via CREB-MSX1 Signaling.

22q11.2 deletion syndrome (22q11.2DS) causes multi-system disorders, among which congenital heart defects are predominant, typically manifesting as conotruncal anomalies. Within the deleted 22q11.2 region, several genes have been identified as critical regulators of heart development; however, the functions of most genes in this interval remain poorly understood. Here, we investigated Mrpl40, which encodes the mitochondrial ribosomal protein L40 (MRPL40), to determine its function in cardiac morphogenesis. Deletion of Mrpl40 in neural crest cells (NCCs) resulted in conotruncal defects. Specifically, Mrpl40 deficiency impaired NCC migration, leading to delayed outflow tract (OFT) septation and aberrant rotation. Mechanistically, we found that Mrpl40 loss disrupted CREB phosphorylation, resulting in reduced expression of Msx1, a crucial regulator of NCC migration and differentiation. Collectively, this study demonstrates the pivotal function of mitochondria in NCC behavior and defines the essential role of Mrpl40 in OFT development, and provides new insights to understand the etiology of 22q11.2DS.