Compound mutations in <i>Bmpr1a</i> and <i>Tak1</i> synergize facial deformities via increased cell death

Liu, Xia; Hayano, Satoru; Pan, Haichun; Inagaki, Manabu; Ninomiya‐Tsuji, Jun; Sun, Hongchen; Mishina, Yuji

doi:10.1002/dvg.23093

Cited by 11 publications

(14 citation statements)

References 35 publications

(74 reference statements)

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“…We reported that Tak1 ‐deficient mutants display a round skull, hypoplastic maxilla and mandible, and cleft palate . Interestingly, deletion of Tak1 aggravates the craniofacial deformities of caBmpr1a;P0‐Cre mutants that have craniosynostosis . Those cKO mice die during the perinatal period precluding functional assessment of TAK1 during postnatal tooth development including secondary dentin formation; therefore, addressing the function of TAK1 with inducible gene targeting systems will provide additional insights into how BMP‐non‐Smad signaling regulates postnatal dentinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…(32) Interestingly, deletion of Tak1 aggravates the craniofacial deformities of caBmpr1a; P0-Cre mutants that have craniosynostosis. (33) Those cKO mice die during the perinatal period precluding functional assessment of TAK1 during postnatal tooth development including secondary dentin formation; therefore, addressing the function of TAK1 with inducible gene targeting systems will provide The region was determined from the cemento-enamel junction that extended 100 μm toward coronal direction (crown thickness) or apical direction (root thickness). Reduced crown dentin thickness in the Bmpr1a cKO molars was restored in the compound mutants.…”

Section: Discussionmentioning

confidence: 99%

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BMP‐Smad Signaling Regulates Postnatal Crown Dentinogenesis in Mouse Molar

et al. 2019

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Dentinogenesis, a formation of dentin by odontoblasts, is an essential process during tooth development. Bone morphogenetic proteins (BMPs) are one of the most crucial growth factors that contribute to dentin formation. However, it is still unclear how BMP signaling pathways regulate postnatal crown and root dentinogenesis. BMPs transduce signals through canonical Smad and non‐Smad signaling pathways including p38 and ERK signaling pathways. To investigate the roles of Smad and non‐Smad signaling pathways in dentinogenesis, we conditionally deleted Bmpr1a, which encodes the type 1A receptor for BMPs, to remove both Smad and non‐Smad pathways in Osterix‐expressing cells. We also expressed a constitutively activated form of Bmpr1a (caBmpr1a) to increase Smad1/5/9 signaling activity without altered non‐Smad activity in odontoblasts. To understand the function of BMP signaling during postnatal dentin formation, Cre activity was induced at the day of birth. Our results showed that loss of BmpR1A in odontoblasts resulted in impaired dentin formation and short molar roots at postnatal day 21. Bmpr1a cKO mice displayed a reduction of dentin matrix production compared to controls associated with increased cell proliferation and reduced Osx and Dspp expression. In contrast, caBmpr1a mutant mice that show increased Smad1/5/9 signaling activity resulted in no overt tooth phenotype. To further dissect the functions of each signaling activity, we generated Bmpr1a cKO mice also expressing caBmpr1a to restore only Smad1/5/9 signaling activity. Restoring Smad activity in the compound mutant mice rescued impaired crown dentin formation in the Bmpr1a cKO mice; however, impaired root dentin formation and short roots were not changed. These results suggest that BMP‐Smad signaling in odontoblasts is responsible for crown dentin formation, while non‐Smad signaling may play a major role in root dentin formation and elongation. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BMP‐Smad Signaling Regulates Postnatal Crown Dentinogenesis in Mouse Molar

et al. 2019

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“…Deficient activation of the p38 pathway observed in BMPR1A R406L ‐expressing chondrocytes results in loss of Sox9 expression; however, it may contribute to the apoptosis phenotype observed in our cell culture. Mouse studies have shown that compound mutations in constitutively active Bmpr1a and loss of function of TAK1 (upstream of p38 activation) exacerbate deformities via increased cell death (Liu et al, ). Moreover, loss of noncanonical signaling via TAK1 in developing nasal cartilage results in enhanced p‐Smad1/5/8 levels, a phenotype similar to our cell transfection study (Liu et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The Smads then regulate transcription within the nucleus (Shi & Massagué, ). BMPs are also involved in the activation of TAK1 and downstream effectors including p38 (Greenblatt, Shim, & Glimcher, ; Greenblatt, Shim, Zou, et al, ; Liu et al, ). Bone Morphogenetic Protein Receptor Type1A (BMPR1A) (OMIM: 601299) is one of the crucial membrane receptors of this pathway in skeletal tissues (Rigueur et al, ; Yoon et al, ).…”

Section: Introductionmentioning

confidence: 99%

Homozygous missense variant in BMPR1A resulting in BMPR signaling disruption and syndromic features

Russell

Rigueur

Weaver

et al. 2019

Molec Gen & Gen Med

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BackgroundThe bone morphogenetic protein (BMP) pathway is known to play an imperative role in bone, cartilage, and cardiac tissue formation. Truncating, heterozygous variants, and deletions of one of the essential receptors in this pathway, Bone Morphogenetic Protein Receptor Type1A (BMPR1A), have been associated with autosomal dominant juvenile polyposis. Heterozygous deletions have also been associated with cardiac and minor skeletal anomalies. Populations with atrioventricular septal defects are enriched for rare missense BMPR1A variants.MethodsWe report on a patient with a homozygous missense variant in BMPR1A causing skeletal abnormalities, growth failure a large atrial septal defect, severe subglottic stenosis, laryngomalacia, facial dysmorphisms, and developmental delays.ResultsFunctional analysis of this variant shows increased chondrocyte death for cells with the mutated receptor, increased phosphorylated R‐Smads1/5/8, and loss of Sox9 expression mediated by decreased phosphorylation of p38.ConclusionThis homozygous missense variant in BMPR1A appears to cause a distinct clinical phenotype.

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“…Particularly, our recent studies demonstrated that both P0-Cre and Wnt1-Cre differentially target neural crest cells emerging at the anterior, middle and posterior portions of the head during embryogenesis ( Chen et al, 2017 ). Previously, we reported a neural crest-specific disruption of TGF-beta activating kinase 1 ( Tak1 ) using Wnt1 - Cre and P0 - Cre , respectively ( Yumoto et al, 2013 ; Liu et al, 2018 ). While Tak1 P0 mutants do not show overt craniofacial phenotypes at birth ( Liu et al, 2018 ), Tak1 Wnt1 mutants develop cleft palate secondarily to the micrognathia ( Yumoto et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

A Ciliary Protein EVC2/LIMBIN Plays a Critical Role in the Skull Base for Mid-Facial Development

et al. 2018

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Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplastic disorder. Affected patients present a wide spectrum of symptoms including short stature, postaxial polydactyly, and dental abnormalities. We previously disrupted Evc2, one of the causative genes for EvC syndrome, in mice using a neural crest-specific, Cre-mediated approach (i.e., P0-Cre, referred to as Evc2 P0 mutants). Despite the fact that P0-Cre predominantly targets the mid-facial region, we reported that many mid-facial defects identified in Evc2 global mutants are not present in Evc2 P0 mutants at postnatal day 8 (P8). In the current study, we used multiple Cre lines (P0-Cre and Wnt1-Cre, respectively), to specifically delete Evc2 in neural crest-derived tissues and compared the resulting mid-facial defects at multiple time points (P8 and P28, respectively). While both Cre lines indistinguishably targeted the mid-facial region, they differentially targeted the anterior portion of the skull base. By comprehensively analyzing the shapes of conditional mutant skulls, we detected differentially affected mid-facial defects in Evc2 P0 mutants and Evc2 Wnt1 mutants. Micro-CT analysis of the skull base further revealed that the Evc2 mutation leads to a differentially affected skull base, caused by premature closure of the intersphenoid synchondrosis (presphenoidal synchondrosis), which limited the elongation of the anterior skull base during the postnatal development of the skull. Given the importance of the skull base in mid-facial bone development, our results suggest that loss of function of Evc2 within the skull base secondarily leads to many aspects of the mid-facial defects developed by the EvC syndrome.

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

Cited by 11 publications

References 35 publications

BMP‐Smad Signaling Regulates Postnatal Crown Dentinogenesis in Mouse Molar

BMP‐Smad Signaling Regulates Postnatal Crown Dentinogenesis in Mouse Molar

Homozygous missense variant in BMPR1A resulting in BMPR signaling disruption and syndromic features

A Ciliary Protein EVC2/LIMBIN Plays a Critical Role in the Skull Base for Mid-Facial Development

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