Early increased cell proliferation compensates subsequent hypoplasia of the ossicle

Ossicles are essential structures for normal sound conduction from the external environment to the inner ear. Proper formation of the ossicles is required for normal hearing, and ossicular deformities lead to hearing loss. We identified ossicular hypoplasia in mice with mesenchymal conditional deletion of the primary cilia molecule (<i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i> and <i>Ift88</i> ^<i>fl/fl</i> <i>;Wnt1Cre</i>). Hh signaling activity and cell proliferation were significantly downregulated in ossicle primordia of <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i> mice from E11.5. To restore Hh signaling in <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i> mice, we crossed <i>R26SmoM2</i> ^<i>fl</i> mice (a constitutively active form of Smo) with <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i> mice. Ossicular hypoplasia was partially rescued in <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i>;<i>R26SmoM2</i> ^<i>fl</i> mice. However, Hh signaling activity was not restored after E11.5. Instead, Hh signaling activity and cell proliferation were significantly increased in <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i>;<i>R26SmoM2</i> ^<i>fl</i> mice at E10.5, when these were not altered in <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i> mice. To confirm whether molecular changes at E10.5 rescue subsequent hypoplasia, SAG (agonist of Hh signaling) was applied to <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i> mice at E9.5. A similar rescue could be observed in <i>Ofd1</i> ^<i>fl</i> <i>;Wnt1Cre</i> mice with SAG application. Thus, early increased cell proliferation could compensate subsequent hypoplasia of ossicle formation. Our results may provide clues for possible future treatment in familial hearing loss due to hypoplasia of the ossicles.