BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development

Abstract

Craniosynostosis is caused by premature fusion of one or more sutures in an infant skull, resulting in abnormal facial features. The molecular and cellular mechanisms by which genetic mutations cause craniosynostosis are incompletely characterized, and many of the causative genes for diverse types of syndromic craniosynostosis have not yet been identified. We previously demonstrated that augmentation of BMP signaling mediated by a constitutively active BMP type IA receptor (ca-BmpR1A) in neural crest cells (ca1A hereafter) causes craniosynostosis and superimposition of heterozygous null mutation of Bmpr1a rescues premature suture fusion (ca1A;1aH hereafter). In this study, we superimposed heterozygous null mutations of the other two BMP type I receptors, Bmpr1b and Acvr1 (ca1A;1bH and ca1A;AcH respectively hereafter) to further dissect involvement of BMP-Smad signaling. Unlike caA1;1aH, ca1A;1bH and ca1A;AcH did not restore the craniosynostosis phenotypes. In our in vivo study, Smad-dependent BMP signaling was decreased to normal levels in mut;1aH mice. However, BMP receptor-regulated Smads (R-Smads; pSmad1/5/9 hereafter) levels were comparable between ca1A, ca1A;1bH and ca1A;AcH mice, and elevated compared to control mice. Bmpr1a, Bmpr1b and Acvr1 null cells were used to examine potential mechanisms underlying the differences in ability of heterozygosity for Bmpr1a vs. Bmpr1b or Acvr1 to rescue the mut phenotype. pSmad1/5/9 level was undetectable in Bmpr1a homozygous null cells while pSmad1/5/9 levels did not decrease in Bmpr1b or Acvr1 homozygous null cells. Taken together, our study indicates that different levels of expression and subsequent activation of Smad signaling differentially contribute each BMP type I receptor to BMP-Smad signaling and craniofacial development. These results also suggest differential involvement of each type 1 receptor in pathogenesis of syndromic craniosynostoses.

Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model

“…Next, we also measured the sagittal length of the two most anterior bones: the nasal and the frontal bones. We previously reported that both bones are shorter in the caA3 mutant mice in association with a wider distance between the eyes (hypertelorism) (Komatsu et al, ; Pan et al, ). Similar to the distances between bones, nasal bone length and distance between eyes were significantly rescued in the mutant mice in Tx 2 and Tx 3 groups but not in the Tx 1 treatment group (Figure D).…”

“…We used our previously generated transgenic mice that conditionally express a constitutively active form of Bmpr1a ( caBmpr1a , aka caAlk3 ) that develop craniofacial abnormalities including craniosynostosis when crossed with P0 ‐cre mice that express a Cre‐recombinase in a neural crest‐specific promoter (caA3 mutant hereafter) (Hayano, Komatsu, Pan, & Mishina, ; Kamiya et al, ; Komatsu et al, ; Pan et al, ; Yamauchi et al, ). These mice developed premature fusion of cranial sutures including the nasal and the anterior frontal sutures before weaning stage along with a large osseous defect at the level of the posterior frontal suture (Supporting Information Figure 1) (Komatsu et al, ; Pan et al, ). To identify the effect of enhanced BMP signaling on the mesenchymal stem cell population that gives rise to the cranial suture (Zhao et al, ), these mice were crossed with a Gli1 ‐LacZ mouse line, which expresses LacZ in Gli1 expressing cells (Bai, Auerbach, Lee, Stephen, & Joyner, ).…”

“…Noggin, an antagonist of BMP, is expressed in patent sutures and ectopic expression prevents normal fusion of posterior frontal suture (Greenwald et al, ; Warren et al, ). Our previous work demonstrated that a small increase in BMP‐SMAD signaling in mouse neural crest cells leads to premature fusion of the anterior frontal suture, which can be rescued by Bmpr1a heterozygosity (Komatsu et al, ; Pan et al, ).…”

BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells

“…BMPRII is constitutively active and can phosphorylate and activate BMPRI upon ligand binding. All the BMPRI molecules, BMPRIA, BMPRIB and ACVR1, have been shown to contribute to skeletal development 15 , 18 – 21 . It has been reported that Bmpr1a , when overexpressed, successfully rescues the differentiation defect of chondrocytes due to deletion of Bmpr1b 22 , suggesting that they have redundant functions.…”

“…Previous studies have revealed vital roles of BMPs and their receptors in osteoblast and chondrocyte differentiation and bone formation during skeletal development 11 , 16 , 18 , 23 . Conventional knockout mice for Bmpr1a show early embryonic lethality 24 .…”