Fig. 6. A model of the functional hierarchy of COUP-TFI modulation of Notch signaling in hair cell and support cell differentiation. In the wild type, Lfng modulates Notch activities by limiting Notch ligand-receptor interactions. This process is regulated by the restricted expression of Lfng that allows strong binding of Notch with ligands such as Jag1, which promotes Notch signaling and the expression of downstream target genes, such as Hes5. Hes5 inhibits the expression of Math1, leading to a normal limit of hair cell and support cell differentiation. COUP-TFI may directly modulate these Notch components in regulating hair cell and support cell differentiation. The absence of COUP-TFI results in expansion of the Lfng expression domain and an increasing inhibition of Notch ligand-receptor interactions, and results in a reduced expression of Hes5. Reduced Hes5 levels have a less inhibitory effect on Math1 transcription, which allows Math1 to induce extra hair cell differentiation.