Follistatin controls the number of murine teeth by limiting TGF-β signaling

Supernumerary teeth are common developmental anomalies of dentition. However, the factors and mechanisms driving their formation remain largely unknown. Here, we report that conditional knockout of <i>Fst</i>, encoding an antagonist for the transforming growth factor β (TGF-β) signaling pathway, in both oral epithelium and mesenchyme of mice (<i>Fst</i> ^<i>CKO</i> ) led to supernumerary upper incisor teeth, arising from the lingual dental epithelium of the native teeth and preceded by an enlarged and split lingual cervical loop. <i>Fst-</i>deficiency greatly activated TGF-β signaling in developing maxillary incisor teeth, associated with increased epithelium cell proliferation. Moreover, <i>Fst</i> ^<i>CKO</i> teeth exhibited increased expression of <i>Tbx1</i>, <i>Sp6</i>, and <i>Sox2</i>, which were identified as direct targets of TGF-β/SMAD2 signaling. Finally, we show that upregulation of <i>Tbx1</i> in response to <i>Fst</i>-deficiency was largely responsible for the formation of extra teeth in <i>Fst</i> ^<i>CKO</i> mice. Taken together, our investigation indicates a novel role for <i>Fst</i> in controlling murine tooth number by restricting TGF-β signaling.