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

分泌的蛋白质指导骨骼元素的起始、生长和形成模式。 BMP是这些因素的重要例子。BMP家族成员在15年前通过其在实验环境中诱导骨的能力首次被鉴定。然而，令人惊讶的是，很少有人知道这个家族的不同成员在正常的软骨形成和骨形成过程中发挥的确切作用。这是一个复杂的问题，因为在不同的BMP家族成员之间可能存在显著的功能冗余。BMP可能在骨骼形成的不同步骤中发挥多种作用，使得后期阶段更难评估，此外，其中几种BMP基因的功能丧失会导致在骨骼表型评估之前早期胚胎死亡。我们将采取遗传学的方法来解决这个问题， 小鼠，利用BMP 2和BMP 4的条件等位基因和BMP 7的无效等位基因。通过从已知在骨骼形成的各个步骤驱动表达的启动子表达ere重组酶，这些基因的功能将被单独或组合地去除。特别是，我们将利用现有的Prx 1：：cre细胞系在肢体软骨形成之前去除BMP活性，而科尔：：ere细胞系去除它们在无骨骨骼内成骨细胞中的活性。类似地，这些基因活性将在神经嵴衍生的颅面骨骼祖细胞中去除，Wntl：：cre和Col：：cre将再次用于研究BMP在真皮骨形成中的作用。真皮骨形成的细胞事件知之甚少。我们将使用鸡系统来识别真皮骨化过程中不同中间细胞类型的标记， 确定生长因子表达的时间和位置，并使用鸡的病毒错误表达来研究它们在调节真皮骨形成中的作用。

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.