Epigenetic regulation of mesenchymal BMP signaling directs postnatal organ innervation

Sensory innervation of developing organs is influenced by molecular cues secreted from surrounding tissues, yet the mechanisms coordinating this tissue-tissue communication are not well understood. Tooth innervation during root development provides a valuable model to investigate how local mesenchymal cues regulate axonal growth under physiological conditions, as innervation begins and progresses alongside tooth root formation. Here we identify the histone demethylase KDM6B, expressed in cranial neural crest-derived dental mesenchyme, as a critical extrinsic regulator of tooth sensory innervation. Loss of Kdm6b in dental mesenchyme severely impairs trigeminal axon entry and branching into the dental pulp, leading to tooth root development defects. Mechanistically, loss of Kdm6b reduces the expression of bone morphogenetic protein (BMP) pathway antagonist Bambi in the dental mesenchyme by modulating H3K27me3 chromatin marks, causing overactivation of BMP signaling, which then directly suppresses the expression of nerve growth factor (Ngf). Compromised NGF activity thereby diminishes mesenchymal support for sensory axon extension during tooth root development. Haploinsufficiency of Ezh2, which antagonizes Kdm6b, or Bmpr1a, a key BMP receptor, partially rescues Ngf expression, sensory innervation, and tooth root development defects in Kdm6b mutants. Together, these findings reveal that epigenetic regulation within mesenchymal cells governs sensory innervation during organogenesis, uncovering important regulatory mechanisms that may inform future strategies for restoring innervation in tissue regenerative approaches.