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Altered BMP-Smad4 signaling causes complete cleft palate by disturbing osteogenesis in palatal mesenchyme

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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 down-regulated, 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.

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Funding

This work was supported by National Natural Science Foundation of China (Grant Numbers: 81771055 and 81970922).

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Author notes

  1. Nan Li, Jing Liu and Han Liu contributed equally to this work.

Authors and Affiliations

  1. Dalian Key Laboratory of Basic Research in Oral Medicine, School of Stomatology, Dalian Medical University, Dalian, 116044, China

    Nan Li, Han Liu, Jing Xiao & Chao Liu

  2. Department of Oral Pathology, School of Stomatology, Dalian Medical University, Dalian, 116044, China

    Nan Li, Jing Liu, Han Liu, Shangqi Wang, Ping Hu, Hailing Zhou, Jing Xiao & Chao Liu

  3. Medical Department of Dandong Stomatological Hospital, Dandong, 118002, China

    Jing Liu

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  1. Nan Li
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Correspondence to Chao Liu.

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Ethical approval

All the experimental procedures involving mice were performed according to the NIH Guideline for the Care and Use of Laboratory Animals (NIH Publication, 8th Edition. Revised 2011). The protocol was inspected and approved by the Animal Care and Use Committee at Dalian Medical University (Approval NO. AEE17038).

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Supplementary Fig. 1

The appearance of Wnt1-cre;pMes-Noggin and Osr2-creKI;pMes-Noggin mice. The black arrow and triangle in (a) indicated the ear and eye, respectively; the red triangle in (b) indicated the truncated forelimb bud. The red arrows in c-f indicated the mandibles; the black triangle in (d) pointed to the open eyelid. (TIF 6085 kb)

Supplementary Fig. 2

The appearance of Osr2-creKI;pMes-caBmpr1a mice. The white and black arrows in a-d indicated the mandibles. (TIF 4763 kb)

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Li, N., Liu, J., Liu, H. et al. Altered BMP-Smad4 signaling causes complete cleft palate by disturbing osteogenesis in palatal mesenchyme. J Mol Histol 52, 45–61 (2021). https://doi.org/10.1007/s10735-020-09922-4

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  • DOI: https://doi.org/10.1007/s10735-020-09922-4

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