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The role of BMP signaling in craniofacial cartilage development

BMP信号在颅面软骨发育中的作用

基本信息

批准号：
9449432
负责人：
Yoshihiro Komatsu
金额：
$ 36.58万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9449432
关键词：
ACVR1 gene Affect BMPR1A gene Bone Development Bone Morphogenetic Proteins Cartilage Cells Cephalic Chondrocytes Chondrogenesis Cilia Cleft Lip Congenital Abnormality Craniofacial Abnormalities Craniosynostosis Defect Development Embryo Etiology FRAP1 gene Face Genetic Goals Growth Human Jaw Joint structure of suture of skull Lead Microtubules Molecular Multipotent Stem Cells Mus Mutant Strains Mice Neural Crest Cell Organelles Osteoblasts Pathway interactions Patients Phenotype Physiologic Ossification Procedures Proteins Reporting Role Signal Transduction Signaling Protein Sirolimus Skeletal Development Stem cells Testing Undifferentiated United States Up-Regulation WNT Signaling Pathway base bone morphogenetic protein receptor type I bone morphogenetic protein receptors cartilage development chondrogenesis factor cilium biogenesis craniofacial craniofacial bone craniofacial disorder craniofacial repair effective therapy gain of function mutation loss of function malformation migration mutant novel public health relevance recombinase-mediated cassette exchange skeletal abnormality skeletal disorder smoothened signaling pathway stem cell population transcription factor

项目摘要

PROJECT SUMMARY Craniofacial abnormalities are largely attributed to defects in the formation, migration and differentiation of cranial neural crest cells (CNCCs). Since CNCCs are developmentally plastic, understanding the genetic and molecular pathways controlling the specification of chondrocyte and osteoblast lineages from CNCC is a prerequisite for interpreting the etiology of craniofacial skeletal disorders. After the discovery of bone morphogenetic proteins (BMPs), many elegant studies have revealed their significant role in skeletal development. However, it is still unclear why BMPs are capable of changing the fate and lineage of undifferentiated stem cells of CNCCs toward skeletogenic cells. Especially, despite the importance of BMPs during craniofacial bone development, it is poorly understood how BMP signaling in CNCCs regulates craniofacial cartilage formation. In our preliminary studies, we employed the Cre-LoxP system that controls BMP signaling in a BMP receptor-specific manner in the mouse. It has been reported that gain-of-function mutations in components of the BMP axis cause craniofacial abnormalities in humans. Consistent with this observation, we previously reported that augmentation of BMP signaling in CNCCs through BMPR1A, one of the BMP type I receptors, causes craniosynostosis due to ectopic cartilage formation in cranial sutures. In this proposal, we focus on another BMP type I receptor, ACVR1. Embryos with augmented BMP signaling through ACVR1 in CNCCs (“ACVR1 mutants” hereafter) displayed jaw malformation and cleft lip, which are distinct craniofacial phenotypes from those of BMPR1A mutants. Interestingly, ACVR1 mutants displayed the enhanced cartilage growth in the face with upregulation of Sox9, a key transcription factor for chondrogenesis. Preliminary screenings revealed that the levels of mammalian target of rapamycin (mTOR) were significantly elevated in ACVR1 mutants. Importantly, inhibition of mTOR signaling by rapamycin rescued the craniofacial cartilage malformation in ACVR1 mutants, indicating that mTOR signaling triggered by the augmentation of BMP is responsible for the enhanced endochondral ossification. Of note, primary cilia, which are microtubule-based antenna-like organelles, were enriched in CNCC-derived chondrocytes in ACVR1 mutants, and the suppression of a ciliary protein rescued the craniofacial cartilage abnormalities in ACVR1 mutants. These results suggest that primary cilia in ACVR1 mutants are responsible for the etiology of enhanced cartilage growth in the face. Our central hypothesis here is that BMP signaling through ACVR1 in CNCCs regulates mTOR, which is required for primary cilium formation during craniofacial cartilage development. We will test our hypothesis by pursuing the specific aims (1) To examine how BMP signaling in CNCCs regulates primary cilium formation during chondrogenesis, and (2) To examine how BMP-mTOR-cilia axis governs chondrogenesis during facial development. Our study will uncover the molecular details of how the novel axis of BMP-mTOR-primary cilia in CNCCs is critical for craniofacial cartilage formation.

项目概要颅面部异常很大程度上归因于颅面部形成、迁移和分化的缺陷。颅神经嵴细胞（CNCC）。由于 CNCC 具有发育可塑性，因此了解遗传和 CNCC 控制软骨细胞和成骨细胞谱系规范的分子途径是解释颅面骨骼疾病病因的先决条件。骨头被发现后形态发生蛋白（BMP），许多优雅的研究揭示了它们在骨骼发育中的重要作用发展。然而，目前尚不清楚为什么 BMP 能够改变人类的命运和谱系。 CNCCs的未分化干细胞向成骨细胞转变。特别是，尽管 BMP 很重要在颅面骨发育过程中，人们对 CNCC 中的 BMP 信号如何调节知之甚少颅面软骨的形成。在我们的初步研究中，我们采用了 Cre-LoxP 系统来控制 BMP 中的 BMP 信号传导小鼠中受体特异性的方式。据报道，某些成分的功能获得性突变 BMP 轴导致人类颅面畸形。与这一观察一致，我们之前报道称，通过 BMPR1A（BMP I 型受体之一）增强 CNCC 中的 BMP 信号传导，由于颅骨缝合处异位软骨形成而导致颅缝早闭。在这个提案中，我们重点关注另一种 BMP I 型受体，ACVR1。 CNCC 中通过 ACVR1 增强 BMP 信号传导的胚胎（以下简称“ACVR1突变体”）表现出下颌畸形和唇裂，这是明显的颅面畸形 BMPR1A 突变体的表型。有趣的是，ACVR1 突变体表现出增强的软骨 Sox9（软骨形成的关键转录因子）上调导致面部生长。初步的筛查显示，哺乳动物雷帕霉素靶蛋白（mTOR）的水平显着升高 ACVR1 突变体。重要的是，雷帕霉素抑制 mTOR 信号传导可以挽救颅面软骨 ACVR1 突变体中的畸形，表明 BMP 增强触发的 mTOR 信号传导是负责增强软骨内骨化。值得注意的是，初级纤毛是基于微管的天线状细胞器，在 ACVR1 突变体中富含 CNCC 衍生的软骨细胞，并且抑制睫状蛋白可挽救 ACVR1 突变体中的颅面软骨异常。这些结果表明 ACVR1 突变体中的初级纤毛是软骨增强的病因脸上的生长。我们的中心假设是 CNCC 中通过 ACVR1 的 BMP 信号调节 mTOR，是颅面软骨发育过程中初级纤毛形成所必需的。我们将测试我们的假设是通过追求特定目标 (1) 研究 CNCC 中的 BMP 信号如何调节初级软骨形成过程中纤毛的形成，以及 (2) 检查 BMP-mTOR-纤毛轴如何控制面部发育过程中的软骨形成。我们的研究将揭示 CNCC 中 BMP-mTOR-初级纤毛的新轴如何变化的分子细节对于颅面软骨的形成至关重要。