The Roles of BMP Genes and Morphogenesis of the Appendicular and Dermal Skeletons

BMP 基因的作用以及阑尾和真皮骨骼的形态发生

• 批准号: 7432430
• 负责人: CLIFFORD J. TABIN
• 金额: $ 40.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7432430
• 关键词: Alleles; BMP2 gene; BMP4; BMP7 gene; Biological Models; Bone Development; Cartilage; Chondrogenesis; Complex; Dermal; Development; Differentiation and Growth; Elements; Embryo; Event; Excision; Family member; Funding; Gene Expression; Genes; Genetic; Growth; Growth Factor; Laboratories; Learning; Limb structure; Mediating; Morphogenesis; Mus; Neural Crest; Osteoblasts; Osteogenesis; Pattern; Pattern Formation; Phenotype; Physical condensation; Play; Process; Protein Family; Proteins; Regulation; Retroviral Vector; Role; Screening procedure; Signal Transduction; Signaling Molecule; Skeletal Development; Skeletal system; Skeleton; Staging; System; Viral; Work; bone; bone morphogenic protein; cell type; craniofacial; insight; interest; loss of function; novel; progenitor; promoter; recombinase; research study

Secreted proteins direct the initiation, growth and patterning or the developing skeletal elements. BMPs are important examples of such factors. BMP family members were first identified over 15 years ago by their ability to induce bone in experimental settings. Yet surprisingly little has been learned about the precise roles different members of this family play during normal chondrogenesis and osteogenesis. This is a complex problem, as there is likely to be significant functional redundancy between different BMP family members. BMPs are likely to play multiple roles at distinct steps of skeletal formation making later stages harder to assess and moreover, loss of function of several of these BMP genes results in early embryonic lethality before skeletal phenotypes can be assessed.. We will take a genetic approach to this problem in mice, utilizing conditional alleles of BMP2 and BMP4 and a null allele of BMP7. Function of thse genes will be removed, singly and in combination, by expressing ere recombinase from promoters known to drive expression at various steps of skeletal formation. In particular, we will utilize an existing Prx1::cre line to remove BMP activity prior to chondrogenesis in the limb, and Coll:: ere to remove their activity in osteoblasts within the appendicular skeleton. Similarly, these gene activities will be removed in the neural crest-derived craniofacial skeletal progenitors with a Wntl::cre and Col::cre will again be used to study the roles of BMPs in dermal bone formation. The cellular events of dermal bone formation are very poorly understood. We will use the chick system to identify markers for different intermediate cell types during dermal ossification, determine when and where growth factors are expressed, and use viral misexpression in chick to study their roles in regulating dermal bone formation.

分泌的蛋白质指导起始，生长和模式或发展的骨骼元素。 BMP是此类因素的重要例子。 BMP家族成员在15年前首次通过在实验环境中诱导骨骼的能力来确定。然而，令人惊讶的是，在正常的软骨发生和成骨发生过程中，该家族的不同成员的精确作用几乎没有学到。这是一个复杂的问题，因为不同BMP家族成员之间可能存在明显的功能冗余。 BMP可能会在骨骼形成的不同步骤中扮演多个角色，从而使以后的阶段更难评估，此外，这些BMP基因的功能丧失会导致早期的胚胎致死性，然后可以评估骨骼表型。 小鼠利用BMP2和BMP4的条件等位基因以及BMP7的无效等位基因。通过表达启动子的ERE重组酶从已知在骨骼形成的各个步骤中驱动表达的启动子中，将删除，单独和组合THSE基因的功能。特别是，我们将利用现有的PRX1 :: CRE系在肢体中的软骨形成之前去除BMP活动，然后Coll :: erte :: erse删除其在阑尾骨骼内成骨细胞中的活性。同样，这些基因活性将在具有Wntl :: cre的神经衍生的颅颅骨骼祖细胞中去除，并再次使用CRE :: CRE来研究BMP在真皮骨形成中的作用。真皮骨形成的细胞事件对了解很少。我们将使用小鸡系统在皮肤骨化过程中识别不同中间细胞类型的标记， 确定表达生长因子何时何地，并在雏鸡中使用病毒式变化来研究其在调节真皮骨形成中的作用。