BMP-Dependent Modulation of ROS Generation and Scavenging Controls Interdigital Cell Death

Programmed cell death during embryonic development plays a vital role in shaping limb morphology in amniotes. BMP (bone morphogenetic protein) signaling has been shown to be essential for inducing interdigital cell death, but its relationship with reactive oxygen species (ROS) production, another driver of this process, remains unclear. Here, we show that BMP signaling modulates ROS production, which is required for subsequent cell death in the interdigital regions of chicken hindlimbs. Through transcriptome analyses, we identify the candidate genes encoding molecular machinery potentially involved in ROS production in response to changes in BMP signaling. Our findings suggest that BMP signaling may influence the redox balance by upregulating the genes encoding ROS-generating enzymes such as Nox2 and Nox4 (components of NADPH oxidase), and downregulating the ROS-scavenging enzyme Sod1. Pharmacological inhibition of NADPH oxidase reduces ROS levels and cell death, indicating that ROS production in the chicken interdigital cell regions is at least partially NADPH oxidase-dependent. Together, these results support a model in which BMP signaling is required for the regulation of programmed cell death, at least in part by modulating redox homeostasis.