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Mechanisms of apical expansion in calvarial bone morphogenesis

颅骨骨形态发生中根尖扩张的机制

基本信息

批准号：
10212367
负责人：
RADHIKA P ATIT
金额：
$ 17.29万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212367
关键词：
3-Dimensional Actins Address Apical Behavior Biophysics Bone Growth Brain Calvaria Cell Polarity Cells Cephalic Chemotaxis Congenital Abnormality Craniofacial Abnormalities Craniosynostosis Cues Data Defect Development Devices Dysplasia Embryo Etiology Event Extracellular Matrix Eye Fibronectins Goals Human Image In Vitro Ligands Light Liquid substance Live Birth Magnetism Maps Mesenchymal Mesenchyme Morphogenesis Movement Mus Mutant Strains Mice Natural regeneration Organ Organogenesis Outcome Pathway interactions Pattern Process Property Proteins Role Sensory Signal Pathway Signal Transduction Syndrome Testing Therapeutic Tissues To specify Variant WNT Signaling Pathway base biophysical techniques bone cell behavior cell motility cranium experimental study in vivo insight intercalation intramembranous bone live cell imaging migration mineralization mouse genetics mutant new therapeutic target novel organ growth planar cell polarity progenitor protein expression skeletal dysplasia suture fusion

项目摘要

Congenital skull defects such as craniosynostosis and dysplasias occur in 1/2500 live births with detrimental consequences for brain and sensory organ development. We lack basic understanding of how and why the skull bones grow towards the apex, which impacts the direction of intramembranous mineralization and fusion of sutures. The signaling factors and cellular mechanisms underlying the apical expansion of skull bone progenitors remain unidentified. We recently found mouse skull bone progenitors migrate from the supraorbital arch region to the apex and this movement is disrupted in conditional mesenchyme Wntless mutants, that lack all ligand secretion. We also identified a graded expression of fibronectin extracellular matrix in the cranial mesenchyme that is dependent on mesenchyme Wnts, suggesting cell movement by a process of durotaxis in which cells migrate along a stiffness gradient of fibronectin. This proposal intends to define, in vivo, the role of the cranial mesenchyme non-canonical Wnts in directing cellular polarity and durotaxis. In this multi-PI proposal, we will leverage our integrative expertise in conditional mouse genetics, live cell imaging, and emerging biophysical approaches in vivo to address our central hypothesis that mesenchyme Wnts-dependent fibronectin orients the collective movement of calvarial bone progenitors toward the apex by durotaxis. Towards the hypothesis, in Aim1 we will identify the role of mesenchyme Wnts signaling in regulating cell movement behaviors with live light-sheet imaging. In Aim2, we will test if fibronectin directs a tissue-stiffness gradient and collective movement of SOM cells apically by durotaxis. Key deliverables of this R21 proposal include: 1. Developing a framework of cellular behaviors during calvarial bone morphogenesis, 2. the role of SOM-Wnt as a global spatial cue, and 3. the role of durotaxis driven cell movements on a graded fibronectin matrix during calvarial bone growth. Impact: Currently, we lack a conceptual framework for understanding cell movement in calvarial bone expansion, despite its role in highly prevalent craniosynostosis and cranial skeletal dysplasias. The results from these proof-of-concept experiments will serve as a new paradigm in our understanding of cell movement in 3D in mesenchymal cells and provide us fresh insights into skull bone morphogenesis and congenital defects.

先天性颅骨缺陷如颅缝闭合和发育不良发生率为1/2500

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Apical expansion of calvarial osteoblasts and suture patency is dependent on graded fibronectin cues.

颅骨成骨细胞的顶端扩张和缝线通畅取决于分级的纤连蛋白线索。

DOI：
10.1101/2023.01.16.524278
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Feng,Xiaotian;Molteni,Helen;Gregory,Megan;Lanza,Jennifer;Polsani,Nikaya;Wyetzner,Rachel;Hawkins,MBrent;Holmes,Greg;Hopyan,Sevan;Harris,MatthewP;Atit,RadhikaP
通讯作者：
Atit,RadhikaP