TWISTED GASTRULATION AND MANDIBULAR ARCH MORPHOGENESIS

扭曲的原肠胚形成和下颌骨形态发生

• 批准号: 8080801
• 负责人: Anna Petryk
• 金额: $ 35.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080801
• 关键词: Affect; Apoptosis; Biological Assay; Bone Morphogenetic Proteins; Branchial arch structure; Cells; Cephalic; Child; Chondrogenesis; Complex; Critical Pathways; Defect; Development; Diagnosis; Dysmorphology; Embryo; Endoderm; Environment; Event; Genes; Genetic; Goals; Growth; Human; Implant; Jaw; Knowledge; Lateral; Lead; Mandible; Medial; Mesenchyme; Microarray Analysis; Modeling; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Neural Crest Cell; Neural Fold; Pathogenesis; Pathway interactions; Pattern; Penetrance; Pharyngeal structure; Play; Primitive foregut structure; Primordium; Protein Binding; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Study models; Syndrome; Testing; Work; base; craniofacial; gastrulation; interest; malformation; migration; molecular marker; mouse model; novel; overexpression; programs

DESCRIPTION (provided by applicant): A significant number of human craniofacial syndromes are the result of abnormal development of the first (mandibular) branchial arch (BA1). Most of BA1 mesenchyme is derived from cephalic neural crest cells (NCC) that emerge from the lateral edges of the neural folds, migrate ventrally in close proximity to the developing pharynx, and populate BA1 primordia. At the level of BA1, NCCs receive signals from the local environment that regulate their proliferation, survival, and differentiation. Multiple developmental pathways are involved in regulating morphogenesis of BA1, with bone morphogenetic proteins (BMPs) playing a prominent role. Twsg1 is a secreted protein that binds to BMPs and modulates their activities. We have shown that Twsg1-deficient mice have abnormal morphogenesis of BA1, manifesting as agnathia, with variable degrees of accompanying craniofacial defects. Twsg1 mutant mice also show defects in foregut endoderm suggesting that Twsg1 signaling is necessary for foregut development. Our long-range goal is to understand molecular mechanisms underlying human craniofacial syndromes. The objective of the present study is to characterize the role of Twsg1 in mandibular arch morphogenesis. Our central hypothesis is that Twsg1 is required for morphogenesis of the medial region of BA1 and that foregut endoderm deficiency in Twsg1-/- mice affects patterning of cephalic NCC. The rationale for the proposed research is that knowledge obtained from this study will promote our understanding of the molecular and cellular basis of BA1 patterning that can ultimately lead to better diagnosis of human craniofacial syndromes, which result from abnormal development of BA1. Our studies will also inform how precise regulation of BMP signaling affects complex patterning events, such as those required for mandibular development. The following specific aims will be pursued: 1) Examine cephalic NCC formation and migration and mandibular arch morphogenesis in Twsg1-/- mice by using NCC- and BA1-specific markers, as well as assays of proliferation and apoptosis; 2) Identify genes regulated by Twsg1 signaling in BA1 development by using microarray technology; 3) Identify the cells that are the primary target of Twsg1 gene action in patterning of BA1 by generating endoderm-specific deletion of Twsg1; 4) Understand how excess of Twsg1 affects molecular boundaries of BMP signaling during BA1 morphogenesis by implanting Twsg1-soaked beads into mouse mandibular explants. Lay summary: Abnormal development of the lower jaw is a common finding in children with various craniofacial syndromes. We have identified a gene, Twsg1, that is important for jaw development in mice. Since Twsg1 gene is also present in humans and lower jaw development is similar in mice and humans, this work can lead to better understanding and ultimately diagnosis of human craniofacial syndromes.

描述（由申请人提供）：大量人类颅面综合征是第一（下颌）鳃裂弓（BA1）异常发育的结果。大部分BA1间质来源于神经褶皱外侧边缘出现的头神经嵴细胞（NCC），向腹侧靠近发育中的咽部迁移，并填充BA1原基。在BA1水平上，ncc接收来自局部环境的信号，调节其增殖、存活和分化。BA1的形态发生涉及多种发育途径，其中骨形态发生蛋白（bone morphogenetic proteins, BMPs）发挥着重要作用。Twsg1是一种与bmp结合并调节其活性的分泌蛋白。我们发现，twsg1缺陷小鼠BA1的形态发生异常，表现为agnathia，并伴有不同程度的颅面缺损。Twsg1突变小鼠在前肠内胚层也表现出缺陷，这表明Twsg1信号是前肠发育所必需的。我们的长期目标是了解人类颅面综合征的分子机制。本研究的目的是表征Twsg1在下颌弓形态发生中的作用。我们的中心假设是，BA1内侧区域的形态发生需要Twsg1，并且前肠内胚层缺乏Twsg1-/-小鼠会影响头侧NCC的模式。提出这项研究的基本原理是，从这项研究中获得的知识将促进我们对BA1模式的分子和细胞基础的理解，最终可以更好地诊断由BA1异常发育引起的人类颅面综合征。我们的研究还将告知BMP信号的精确调节如何影响复杂的模式事件，例如下颌发育所需的模式事件。1)通过NCC-和ba1特异性标记物，以及增殖和凋亡测定，检测Twsg1-/-小鼠头侧NCC的形成、迁移和下颌弓的形态发生；2)利用微阵列技术鉴定BA1发育中受Twsg1信号调控的基因；3)通过产生内胚层特异性的Twsg1缺失，确定Twsg1基因作用BA1模式的主要靶细胞；4)通过将浸泡过Twsg1的微球植入小鼠下颌骨外植体，了解过量的Twsg1如何影响BA1形态发生过程中BMP信号的分子边界。

项目成果

The expression of twisted gastrulation in postnatal mouse brain and functional implications.

出生后小鼠大脑中扭曲原肠胚形成的表达及其功能意义。

• DOI: 10.1016/j.neuroscience.2010.05.026
• 发表时间: 2010
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Sun,M;Forsman,C;Sergi,C;Gopalakrishnan,R;O'Connor,MB;Petryk,A
• 通讯作者: Petryk,A

BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization.

• DOI: 10.1016/j.ydbio.2012.10.007
• 发表时间: 2013-01-01
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Forsman CL;Ng BC;Heinze RK;Kuo C;Sergi C;Gopalakrishnan R;Yee D;Graf D;Schwertfeger KL;Petryk A
• 通讯作者: Petryk A

Autosomal dominant mesomandibular fibro-osseous dysplasia: a self-resolving inherited fibro-osseous lesion of the jaws.

常染色体显性中颌骨纤维骨发育不良：颌骨的一种自消性遗传性纤维骨病变。

• DOI: 10.3389/fphys.2012.00458
• 发表时间: 2012
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Koutlas,IoannisG;Forsman,CynthiaL;Kyrkanides,Stephanos;Oetting,WilliamS;Petryk,Anna
• 通讯作者: Petryk,Anna

Distinct populations within Isl1 lineages contribute to appendicular and facial skeletogenesis through the β-catenin pathway.

• DOI: 10.1016/j.ydbio.2014.01.001
• 发表时间: 2014-03-01
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Akiyama, Ryutaro;Kawakami, Hiroko;Taketo, M. Mark;Evans, Sylvia M.;Wada, Naoyuki;Petryk, Anna;Kawakami, Yasuhiko
• 通讯作者: Kawakami, Yasuhiko