骨发育的顺利进行依赖于成骨和破骨两种细胞的平衡。破骨细胞来源于血液中的髓系细胞，已知转录因子PU.1（急性髓系白血病因子）以及原癌基因fms（集落刺激因子1受体)在早期髓系发育及破骨细胞发育中起到关键作用，然而pu.1和fms在调控破骨细胞发育的分子细胞机理以及相互作用方式仍不明确。我们前期工作中鉴定斑马鱼pu.1G242D突变体与fmsj4e1突变体的表型，发现pu.1G242D 和fmsj4e1 单突变体和pu.1G242D；fmsj4e1双突变体骨密度增加、骨髓腔减小等骨发育异常，但是双突变体的表型最为严重。并且，单突变体中的破骨细胞发育异常而成骨细胞发育不受影响，提示pu.1和fms可能协同调控破骨细胞的发育。本项目拟运用细胞学、遗传学及分子生物学等方法来研究pu.1和fms在调控髓系至破骨细胞发育的细胞学机理、遗传互作关系及分子机制。

Bone development is precisely regulated in the balance of formation by osteoblasts and resorption by osteoclasts. Osteoclasts are originated from blood recruited myeloid cells to the bone surface where they undergo differentiation. It is known that the transcription factor Pu.1 can regulate fms in myelopoiesis. However, the cooperation of these two genes on osteoclast development is still unclear. By utilizing pu.1G242D or fmsj4e1 zebrafish mutants, we found that pu.1G242D or fmsj4e1 single mutants had significantly increased bone mineral density and severely reduced marrow cavity area compared with the wild-type, and double mutant showed severer phenotypes than single mutant. Moreover, we confirmed that the decreased resorption function of osteoclast was causative for the abnormity of bone development in single mutants. All these suggested that pu.1 and fms may cooperatively promote osteoclast development. In this proposal, we are going to elucidate the genetic and molecular relationship between pu.1 and fms during osteoclast development.