Search

Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia that exhibited a dramatic upregulation of Hedgehog signaling. Odontoblasts, which are responsive to transforming growth factor beta (TGF-β)/bone morphogenetic protein (BMP) signals, may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a downregulation of BMP signals from Smad4 mutant odontoblasts to the adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERM in keratinocyte-specific Smad4 knockout mice, suggesting a novel mechanism in which reciprocal TGF-β/BMP signaling between odontoblasts and HERS was required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment. [ABSTRACT FROM AUTHOR]

New blood vessels are formed through the assembly or sprouting of endothelial cells (ECs) and become stabilized by the formation of perivascular matrix and the association with supporting mural cells. To investigate the role of endothelial Smad4 in vascular development, we deleted the Smad4 gene specifically in ECs using the Cre-LoxP system. EC-specific Smad4 mutant mice died at embryonic day 10.5 due to cardiovascular defects, including attenuated vessels sprouting and remodeling, collapsed dorsal aortas, enlarged hearts with reduced trabeculae, and failed endocardial cushion formation. Noticeably, Smad4-deficient ECs demonstrated an intrinsic defect in tube formation in vitro. Furthermore, the mutant vascular ECs dissociated away from the surrounding cells and suffered from impaired development of vascular smooth muscle cells. The disturbed vascular integrity and maturation was associated with aberrant expression of angiopoietins and a gap junction component, connexin43. Collectively, we have provided direct functional evidence that Smad4 activity in the developing ECs is essential for blood vessel remodeling, maturation, and integrity. [ABSTRACT FROM AUTHOR]