TY - JOUR
T1 - Trpv5/6 is vital for epithelial calcium uptake and bone formation
AU - Vanoevelen, J.
AU - Janssens, A.C.
AU - Huitema, L.F.
AU - Hammond, C.J.
AU - Metz, J.R.
AU - Flik, G.
AU - Voets, T.
AU - Schulte-Merker, S.
N1 - Reporting year: 2011
PY - 2011
Y1 - 2011
N2 - Calcium is an essential ion serving a multitude of physiological roles. Aside from its role as a second messenger, it is an essential component of the vertebrate bone matrix. Efficient uptake and storage of calcium are therefore indispensable for all vertebrates. Transient receptor potential family, vanilloid type (TRPV)5 and TRPV6 channels are known players in transcellular calcium uptake, but the exact contribution of this pathway is unclear. We used forward genetic screening in zebrafish (Danio rerio) to identify genes essential in bone formation and identified a lethal zebrafish mutant (matt-und-schlapp) with severe defects in bone formation, including lack of ossification of the vertebral column and craniofacial structures. Mutant embryos show a 68% reduction in calcium content, and systemic calcium homeostasis is disturbed when compared with siblings. The phenotype can be partially rescued by increasing ambient calcium levels to 25 mM. We identified the mutation as a loss-of-function mutation in the single orthologue of TRPV5 and 6, trpv5/6. Expression in HEK293 cells showed that Trpv5/6 is a calcium-selective channel capable of inward calcium transport at physiological concentrations whereas the mutant channel is not. Taken together, this study provides both genetic and functional evidence that transcellular epithelial calcium uptake is vital to sustain life and enable bone formation. [KEYWORDS: Animals, Bone Development/genetics/ physiology, Calcium/ metabolism, Embryo, Nonmammalian/metabolism, Epithelium/ embryology/ metabolism, Gene Expression Regulation, Developmental/physiology, HEK293 Cells, Humans, Molecular Sequence Data, Mutation, TRPV Cation Channels/genetics/ metabolism, Zebrafish/ embryology, Zebrafish Proteins/genetics/ metabolism]
AB - Calcium is an essential ion serving a multitude of physiological roles. Aside from its role as a second messenger, it is an essential component of the vertebrate bone matrix. Efficient uptake and storage of calcium are therefore indispensable for all vertebrates. Transient receptor potential family, vanilloid type (TRPV)5 and TRPV6 channels are known players in transcellular calcium uptake, but the exact contribution of this pathway is unclear. We used forward genetic screening in zebrafish (Danio rerio) to identify genes essential in bone formation and identified a lethal zebrafish mutant (matt-und-schlapp) with severe defects in bone formation, including lack of ossification of the vertebral column and craniofacial structures. Mutant embryos show a 68% reduction in calcium content, and systemic calcium homeostasis is disturbed when compared with siblings. The phenotype can be partially rescued by increasing ambient calcium levels to 25 mM. We identified the mutation as a loss-of-function mutation in the single orthologue of TRPV5 and 6, trpv5/6. Expression in HEK293 cells showed that Trpv5/6 is a calcium-selective channel capable of inward calcium transport at physiological concentrations whereas the mutant channel is not. Taken together, this study provides both genetic and functional evidence that transcellular epithelial calcium uptake is vital to sustain life and enable bone formation. [KEYWORDS: Animals, Bone Development/genetics/ physiology, Calcium/ metabolism, Embryo, Nonmammalian/metabolism, Epithelium/ embryology/ metabolism, Gene Expression Regulation, Developmental/physiology, HEK293 Cells, Humans, Molecular Sequence Data, Mutation, TRPV Cation Channels/genetics/ metabolism, Zebrafish/ embryology, Zebrafish Proteins/genetics/ metabolism]
U2 - 10.1096/fj.11-183145
DO - 10.1096/fj.11-183145
M3 - Article
SN - 0892-6638
VL - 25
SP - 3197
EP - 3207
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -