The transcription factors Foxf1 and Foxf2 integrate the SHH, HGF and TGFβ signaling pathways to drive tongue organogenesis.

The tongue is a highly specialized muscular organ with diverse cellular origins, which provides an excellent model for understanding mechanisms controlling tissue-tissue interactions during organogenesis. Previous studies showed that SHH signaling is required for tongue morphogenesis and tongue muscle organization, but little is known about the underlying mechanisms. Here we demonstrate that the Foxf1/Foxf2 transcription factors act in the cranial neural crest cell (CNCC)-derived mandibular mesenchyme to control myoblast migration into the tongue primordium during tongue initiation, and thereafter continue to regulate intrinsic tongue muscle assembly and lingual tendon formation. We performed chromatin immunoprecipitation sequencing analysis and identified Hgf, Tgfb2 and Tgfb3 among the target genes of Foxf2 in the embryonic tongue. Through genetic analyses of mice with CNCC-specific inactivation of Smo or both Foxf1 and Foxf2, we show that Foxf1 and Foxf2 mediate hedgehog signaling-mediated regulation of myoblast migration during tongue initiation and intrinsic tongue muscle formation by regulating the activation of the HGF and TGFβ signaling pathways. These data uncover the molecular network integrating the SHH, HGF and TGFβ signaling pathways in regulating tongue organogenesis.