Altered BMP-Smad4 signaling causes complete cleft palate by disturbing osteogenesis in palatal mesenchyme
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ORIGINAL PAPER
Altered BMP‑Smad4 signaling causes complete cleft palate by disturbing osteogenesis in palatal mesenchyme Nan Li1,2 · Jing Liu2,3 · Han Liu1,2 · Shangqi Wang2 · Ping Hu2 · Hailing Zhou2 · Jing Xiao1,2 · Chao Liu1,2 Received: 25 April 2020 / Accepted: 23 October 2020 © Springer Nature B.V. 2020
Abstract As the major receptor mediated BMP signaling in craniofacial development, Bmpr1a expression was detected in the anterior palatal shelves from E13.5 and the posterior palatal shelves from E14.5. However, inactivating BMP receptor in the mesenchyme only leads to anterior cleft palate or submucous cleft palate. The role of BMP signaling in posterior palatal mesenchyme and palatal osteogenesis is still unknown. In this study, a secreted BMP antagonist, Noggin was over-expressed by Osr2-creKI to suppress BMP signaling intensively in mouse palatal mesenchyme, which made the newborn mouse displaying complete cleft palate, a phenotype much severer than the anterior or submucous cleft palate. Immunohistochemical analysis indicated that in the anterior and posterior palatal mesenchyme, the canonical BMP-Smad4 signaling was dramatically downregulated, while the non-canonical BMP signaling pathways were altered little. Although cell proliferation was reduced only in the anterior palatal mesenchyme, the osteogenic condensation and Osterix distribution were remarkably repressed in the posterior palatal mesenchyme by Noggin over-expression. These findings suggested that BMP-Smad4 signaling was essential for the cell proliferation in the anterior palatal mesenchyme, and for the osteogenesis in the posterior palatal mesenchyme. Interestingly, the constitutive activation of Bmpr1a in palatal mesenchyme also caused the complete cleft palate, in which the enhanced BMP-Smad4 signaling resulted in the premature osteogenic differentiation in palatal mesenchyme. Moreover, neither the Noggin over-expression nor Bmpr1a activation disrupted the elevation of palatal shelves. Our study not only suggested that BMP signaling played the differential roles in the anterior and posterior palatal mesenchyme, but also indicated that BMP-Smad4 signaling was required to be finely tuned for the osteogenesis of palatal mesenchyme. Keywords Palatogenesis · Osteogenesis · BMP signaling · Noggin · Cleft palate · BMP receptor
Introduction Nan Li, Jing Liu and Han Liu contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10735-020-09922-4) contains supplementary material, which is available to authorized users. * Chao Liu [email protected] Jing Xiao [email protected] 1
Dalian Key Laboratory of Basic Research in Oral Medicine, School of Stomatology, Dalian Medical University, Dalian 116044, China
2
Department of Oral Pathology, School of Stomatology, Dalian Medical University, Dalian 116044, China
3
Medical Department of Dandong Stomatological Hospital, Dandong 118002, China
Cleft palate is the most common congenital defect in human newborns (Mossey and
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