Fgf signaling in patterning of the calvarial joints

颅骨关节模式中的 Fgf 信号传导

• 批准号: 10585820
• 负责人: Amy E Merrill
• 金额: $ 46.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585820
• 关键词: Address; Affect; Alleles; Anterior; Birth; Brain; Calvaria; Cells; Chromatin; Congenital abnormal Synostosis; Connective Tissue; Connective Tissue Cells; Craniosynostosis; Cues; Data; Deformity; Development; Developmental Bone Diseases; Disease; Disease model; Fibroblast Growth Factor Receptor 2; Fibroblasts; Funding; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genomics; Geometry; Growth; In Situ Hybridization; Infant; Joints; Legal patent; Ligaments; Link; Mediating; Mesoderm; Modeling; Molecular Profiling; Morphology; Mus; Nature; Neural Crest Cell; Nuclear; Pathology; Patients; Pattern; Phenotype; Play; Predisposition; Process; Regulation; Research; Role; Shapes; Signal Pathway; Signal Transduction; Specific qualifier value; Structure of fontanel of skull; Surgical sutures; Syndrome; TP53 gene; Technology; Tendon structure; Testing; Tretinoin; Variant; WNT Signaling Pathway; bone; craniofacial; cranium; gain of function; improved; joint formation; loss of function; member; mouse genetics; mouse model; multiple omics; novel; premature; recruit; regional difference; single-cell RNA sequencing; suture fusion; transcriptome sequencing; treatment and outcome

PROJECT SUMMARY The calvarial bones of the infant skull are separated by fibrous connective tissue joints called sutures and fontanelles. These joints are critical for early reshaping of the skull during birth and brain growth. Improper fusion of these joints, both premature and delayed, results in craniofacial deformities seen in numerous genetic disorders. In this proposal, we aim to study the relatively uncharacterized role of calvarial connective tissue (CT) to better understand its role in calvarial joint development and pathology. We hypothesize that lineage-dependent, regional signaling from CT orchestrates distinct differences in morphology, mechanism of fusion, and susceptibility to abnormal closure among calvarial joints. Using both cutting-edge multiomics technology and mouse genetics, we will resolve differences across calvarial joint CTs in both normal and disease contexts. Syndromes featuring premature suture fusion (craniosynostosis) and delayed fontanelle closure are commonly associated with variants in Fibroblast growth factor receptor 2 (FGFR2). Although most research thus far has focused exclusively on the role of Fgfr2 in the bone, our lab has revealed its importance in developing joint CT, including tendon and ligament. We will, therefore, apply these findings to study the role of Fgfr2 in calvarial CT using both loss- and gain-of-function alleles in mice. Our preliminary data shows that Fgfr2 loss-of-function in the neural crest cells (NCC) blocks normal contribution of CT fibroblasts to the advancing bone fronts in the anterior fontanelle (AF) resulting in its patency. Conversely, our gain-of-function model featuring the Fgfr2M391R variant in Bent bone dysplasia syndrome (BBDS) shows that activation in the NCC leads to multi-suture synostosis, most interestingly in sutures where only CT (and not bone) is NCC- derived. Conversely, Fgfr2M391R activation in mesoderm does not affect suture patency. The NCC-specific nature of these phenotypes suggests regional, lineage-dependent regulation of CT. In this proposal, we aim to identify and characterize gene expression and regulatory networks within CT fibroblast subtypes, as well as their spatial arrangements and fate trajectories, in different sutures and fontanelles. We predict that regional regulation of Wnt, Fgf, and retinoic acid signaling pathways play a key role in the organization and fusion of normal sutures by affecting cell fate potential. Additionally, we will explore the novel concept that non- canonical, nuclear signaling of Fgfr2 orchestrates these processes via differential gene regulation in calvarial CT fibroblasts. This study is expected to show that CT fibroblasts are signaling centers that direct calvarial joint development and underlie region-specific fusion patterns in congenital skull deformities.

项目摘要 婴儿头骨的颅骨被称为缝合线的纤维结缔组织关节分开， 前囟这些关节对于出生和大脑生长期间头骨的早期重塑至关重要。不当 这些关节的融合，无论是过早的还是延迟的，都会导致颅面畸形， 遗传疾病在这个建议中，我们的目的是研究相对不典型的作用，颅骨连接 组织（CT），以更好地了解其在颅关节发育和病理学中的作用。我们假设 来自CT的谱系依赖性区域信号传导协调了形态学、机制 颅关节易发生异常闭合。利用尖端的多组学技术 技术和小鼠遗传学，我们将解决正常和 疾病背景。以过早缝合融合（颅缝早闭）和延迟<$门为特征的合缝 闭合通常与成纤维细胞生长因子受体2（FGFR 2）的变体相关。虽然大多数 到目前为止，研究只集中在Fgfr 2在骨骼中的作用，我们的实验室已经揭示了它的重要性。 包括肌腱和韧带的关节CT。因此，我们将应用这些发现来研究 Fgfr 2在使用小鼠功能丧失和获得等位基因的颅骨CT中的作用。我们的初步数据显示 Fgfr 2在神经嵴细胞（NCC）中的功能丧失阻断了CT成纤维细胞对细胞增殖的正常贡献。 推进前囟（AF）中的骨前缘，导致其开放。相反，我们的功能增益 以Fgfr 2 M391 R变异体为特征的Bent骨发育不良综合征（BBDS）模型显示， NCC导致多缝线骨性结合，最有趣的是只有CT（而不是骨）是NCC的缝线。 推导相反，中胚层中的Fgfr 2 M391 R活化不影响缝线通畅性。NCC具体 这些表型的性质表明CT的区域性、谱系依赖性调节。在本建议中，我们的目标是 鉴定和表征CT成纤维细胞亚型内的基因表达和调控网络，以及 它们的空间排列和命运轨迹，在不同的缝和fontanelles。我们预测， Wnt、Fgf和视黄酸信号通路的调节在细胞的组织和融合中起关键作用。 影响细胞命运的可能性。此外，我们将探讨新的概念，非- 典型的，Fgfr 2的核信号通过颅骨中的差异基因调控协调这些过程。 CT成纤维细胞。这项研究有望表明CT成纤维细胞是指导颅骨的信号中心， 先天性颅骨畸形中关节发育和潜在区域特异性融合模式

项目成果

Clinical and radiographic delineation of Bent Bone Dysplasia-FGFR2 type or Bent Bone Dysplasia with Distinctive Clavicles and Angel-shaped Phalanges.

• DOI: 10.1002/ajmg.a.37772
• 发表时间: 2016-10
• 期刊: American journal of medical genetics. Part A
• 作者: Krakow D;Cohn DH;Wilcox WR;Noh GJ;Raffel LJ;Sarukhanov A;Ivanova MH;Danielpour M;Grange DK;Elliott AM;Bernstein JA;Rimoin DL;Merrill AE;Lachman RS
• 通讯作者: Lachman RS

Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease.

• DOI: 10.1007/s11914-019-00512-2
• 发表时间: 2019-06
• 期刊: Current osteoporosis reports
• 影响因子: 4.3
• 作者: Tuzon CT;Rigueur D;Merrill AE
• 通讯作者: Merrill AE

A requirement for Fgfr2 in middle ear development.

中耳发育对 Fgfr2 的要求。

• DOI: 10.1002/dvg.23252
• 发表时间: 2019
• 期刊: Genesis (New York, N.Y. : 2000)
• 作者: Rigueur,Diana;Roberts,RyanR;Bobzin,Lauren;Merrill,AmyE
• 通讯作者: Merrill,AmyE

FGF signaling patterns cell fate at the interface between tendon and bone.

FGF 信号传导模式决定肌腱和骨骼之间界面的细胞命运。

• DOI: 10.1242/dev.170241
• 发表时间: 2019
• 期刊: Development (Cambridge, England)
• 作者: Roberts,RyanR;Bobzin,Lauren;Teng,CamillaS;Pal,Deepanwita;Tuzon,CreightonT;Schweitzer,Ronen;Merrill,AmyE
• 通讯作者: Merrill,AmyE