The aim of this proposal is to define the role of Bicaudal-C homolog 1 (Bicc1) in bone. Using an innovative systems genetics approach in the mouse we predicted that Bicc1 was the basis of a BMD quantitative trait locus (QTL). Bicc1 is an RNA-binding protein that has been implicated in the regulation of primary cilia. In this proposal, we demonstrate that jcpk mice, which are heterozygous for a Bicc1 null allele, are osteopenic and that genetic variants in human BICC1 gene are associated with BMD. Moreover, Bicc1 is highly expressed in differentiating osteoblasts and Bicc1 knockdown in primary calvarial osteoblasts impairs differentiation. We also show that Bicc1 regulates Pkd2, which is thought to be a critical component of the primary cilia on osteoblasts. Based on these data we hypothesize that Bicc1 influences BMD through an osteoblast and Pkd2 dependent mechanism.
In Specific Aim 1 a series of in vitro and in vivo interaction experiments will be used to determine if the actions of Bicc1 on osteoblast differentiation and BMD are via the regulation of Pkd2 levels.
In Specific Aim 2 we will determine if Bicc1 regulates BMD in an osteoblast-specific manner. This will be accomplished by ablating Bicc1 in osteoblasts using the cre-loxP technology and characterizing bone mass using microCT and histomorphometry. Transcriptional network analysis will also be used to further characterize Bicc1 function. The proposed studies will significantly advance our understanding of a novel BMD gene.
Successful completion of this proposal will begin to reveal how Bicc1, a novel BMD gene, affects bone mass. It also has the potential to advance our understanding of a novel mechanism regulating primary cilia function in bone.
|Lusis, Aldons J; Seldin, Marcus M; Allayee, Hooman et al. (2016) The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits. J Lipid Res 57:925-42|
|Calabrese, Gina; Mesner, Larry D; Foley, Patricia L et al. (2016) Network Analysis Implicates Alpha-Synuclein (Snca) in the Regulation of Ovariectomy-Induced Bone Loss. Sci Rep 6:29475|
|Calabrese, Gina M; Mesner, Larry D; Stains, Joseph P et al. (2016) Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module. Cell Syst :|
|Frey, Julie L; Li, Zhu; Ellis, Jessica M et al. (2015) Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. Mol Cell Biol 35:1979-91|
|Song, Woo-Jin; Mondal, Prosenjit; Wolfe, Andrew et al. (2014) Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab 19:667-81|
|Mesner, Larry D; Ray, Brianne; Hsu, Yi-Hsiang et al. (2014) Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density. J Clin Invest 124:2736-49|
|Farber, Charles R; Reich, Adi; Barnes, Aileen M et al. (2014) A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor. J Bone Miner Res 29:1402-11|
|Farber, Charles R (2013) Systems-level analysis of genome-wide association data. G3 (Bethesda) 3:119-29|
|Leamy, Larry J; Kelly, Scott A; Hua, Kunjie et al. (2013) Quantitative trait loci for bone mineral density and femoral morphology in an advanced intercross population of mice. Bone 55:222-9|
|Ghazalpour, Anatole; Rau, Christoph D; Farber, Charles R et al. (2012) Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits. Mamm Genome 23:680-92|
Showing the most recent 10 out of 13 publications