Upf3a-dependent genetic compensation sustains BMP robustness during murine odontogenesis

However, direct in vivo evidence for HDGCR in mammal species remains limited. Bone morphogenetic protein (BMP) signaling is indispensable for murine tooth development, yet extensive ligand redundancy frequently masks phenotypes in single-gene knockouts, making odontogenesis an ideal organ system to interrogate HDGCR.

Here, we generated a conditional Upf3a knockout mouse (Upf3af/f), exhibiting normal survival and tooth development when crossed with Wnt1-Cre mice, for in vivo HDGCR studies. Loss of Upf3a abolished the compensatory upregulation of paralogous Bmp4 following Bmp2 deletion, functionally mimicking a Bmp2/Bmp4 double-deficient state. This disruption promoted proliferation of dental pulp cells and root progenitor cells and inhibited differentiation of odontoblasts, leading to severe defects in dentinogenesis and root development.