The role of IFT80 in bone formation

描述（由申请人提供）：鞭毛内运输（IFT）蛋白是基于微管的运输机械，对所有纤毛和鞭毛的组装和维护至关重要。近年来的研究不仅揭示了纤毛和鞭毛在运动、感觉接受和信号传导等方面的多种作用，而且还证实了IFT在基因调控和表达、细胞增殖和分化以及动物发育和行为等方面的调控作用。IFT蛋白的突变导致各种生物体纤毛和鞭毛的丢失或严重减少，从而导致以肾脏、视网膜和骨骼病理改变的各种组合为特征的许多人类疾病。条件消融IFT88会破坏刺猬信号，导致多指畸形和软骨内骨形成缺陷。Kif3a（运动蛋白II的一个亚基）的破坏会导致肢体和颅骨骨骼异常。最近，在Ellis-van Creveld综合征（EVC）软骨外胚层发育不良（chondroectodermal dysplasia， EVC）中发现了一种新的蛋白突变，该蛋白位于纤毛基部，在小鼠中，该基因的破坏会导致各种骨骼和颅面异常

DESCRIPTION (provided by applicant): Intraflagellar transport (IFT) proteins are microtubule based transport machinery, which are essential for the assembly and maintenance of all cilia and flagella. Recent findings have not only revealed the various roles of cilia and flagella in motility, sensory reception, and signaling, but also demonstrated the function of IFT in the control of gene regulation and expression, cell proliferation and differentiation, and animal development and behavior. The mutation of IFT proteins causes the loss or severe reduction of cilia and flagella in various organisms, which can lead to numerous human diseases characterized by various combinations of pathological changes of kidney, retina, and skeleton. Conditional ablation of IFT88 disrupts hedgehog signaling, with polydactyly and defects of endochondral bone formation. Disruption of Kif3a, a subunit of kinesin II, showed limb and cranial skeletal abnormalities. Recently, a novel protein mutated in chondroectodermal dysplasia Ellis-van Creveld syndrome (EVC) was found to be localized to the base of the cilia, and disruption of this gene in mice results in a variety of skeletal and craniofacial abnormalities as well as alterations in the teeth and nails. Mice with targeted deletion of IFT/cilia have a wide variety of bone phenotypes that provide interesting insights into the function of individual IFT protein in bone formation. Most recently, Beales et al group found that the partial loss of IFT80 in human, a novel component of the IFT complex B, causes human diseases such as Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III. Both diseases have severe bone abnormalities including shortening of the long bones and constriction of the thoracic cage. However, it is unclear how IFT80 mutation leads to skeletal abnormalities. Our recent studies have shown that IFT80 is highly expressed during osteoblast differentiation. Silencing IFT80 not only impairs cilia formation, but also significantly inhibits osteoblast differentiation through down-regulating the expression of osteoblast marker genes- Runx2 and osteocalcin, and hedgehog signaling (Hh) related genes -shh, Ihh and Gli2. These are important results; nonetheless, there is still no in vivo evidence for a general requirement for IFT80 signaling in osteoblast differentiation and bone formation. Most recently, we have generated IFT80 conditional knockout model in osteoblast specific lineage and found that IFT80 mutant mice showed apparent growth retardation with severe bone abnormalities. Based on these results, we hypothesize that IFT80 plays an essential role in vertebrate bone formation and normal bone function through regulating osteoblast gene expression, differentiation and Hh/Gli pathway. In this proposal, we will test the hypothesis by generating an IFT80 conditional knockout allele to study the role of IFT80 in bone formation and investigating the effect of deletion of this gene on osteoblast gene expression, differentiation and proliferation. The long term objective of this work is to understand the functionmechanism and interactions of IFT/cilia proteins in bone development and bone diseases.