Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death

Xia Liu, Satoru Hayano, Haichun Pan, Maiko Inagaki, Jun Ninomiya-Tsuji, Hongchen Sun, Yuji Mishina

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

BMP signaling plays a critical role in craniofacial development. Augmentation of BMPR1A signaling through neural crest-specific expression of constitutively active Bmpr1a (caBmpr1a) results in craniofacial deformities in mice. To investigate whether deletion of Tak1 may rescue the craniofacial deformities caused by enhanced Smad-dependent signaling through caBMPR1A, we generated embryos to activate transcription of caBmpr1a transgene and ablate Tak1 in neural crest derivatives at the same time. We found that deformities of the double mutant mice showed more severe than those with each single mutation, including median facial cleft and cleft palate. We found higher levels of cell death in the medial nasal and the lateral nasal processes at E10.5 in association with higher levels of p53 in the double mutant embryos. We also found higher levels of pSmad1/5/9 in the lateral nasal processes at E10.5 in the double mutant embryos. Western analyses revealed that double mutant embryos showed similar degrees of upregulation of pSmad1/5/9 with caBmpr1a or Tak1-cKO embryos while the double mutant embryos showed higher levels of phospho-p38 than caBmpr1a or Tak1-cKO embryos at E17.5, but not at E10.5. It suggested that deletion of Tak1 aggravates the craniofacial deformities of the caBmpr1a mutants by increasing p53 and phospho-p38 at different stage of embryogenesis.

Original languageEnglish
Article numbere23093
JournalGenesis
Volume56
Issue number3
DOIs
Publication statusPublished - Mar 2018

Keywords

  • MAP kinase
  • Smad signaling
  • apoptosis
  • facial prominence
  • nasal septum

ASJC Scopus subject areas

  • Genetics
  • Endocrinology
  • Cell Biology

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    Liu, X., Hayano, S., Pan, H., Inagaki, M., Ninomiya-Tsuji, J., Sun, H., & Mishina, Y. (2018). Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death. Genesis, 56(3), [e23093]. https://doi.org/10.1002/dvg.23093