Gene disruption of Spred-2 causes dwarfism
Standard
Gene disruption of Spred-2 causes dwarfism. / Bundschu, Karin; Knobeloch, Klaus-Peter; Ullrich, Melanie; Schinke, Thorsten; Amling, Michael; Engelhardt, Catherine M; Renné, Thomas; Walter, Ulrich; Schuh, Kai.
in: J BIOL CHEM, Jahrgang 280, Nr. 31, 05.08.2005, S. 28572-80.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Gene disruption of Spred-2 causes dwarfism
AU - Bundschu, Karin
AU - Knobeloch, Klaus-Peter
AU - Ullrich, Melanie
AU - Schinke, Thorsten
AU - Amling, Michael
AU - Engelhardt, Catherine M
AU - Renné, Thomas
AU - Walter, Ulrich
AU - Schuh, Kai
PY - 2005/8/5
Y1 - 2005/8/5
N2 - The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase (MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2(-/-) mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2(-/-) chondrocytes in comparison to Spred-2(+/+) chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.
AB - The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase (MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2(-/-) mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2(-/-) chondrocytes in comparison to Spred-2(+/+) chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.
KW - Animals
KW - Bone Development
KW - Dwarfism
KW - Female
KW - Gene Deletion
KW - Genetic Vectors
KW - Humans
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Repressor Proteins
KW - Reverse Transcriptase Polymerase Chain Reaction
U2 - 10.1074/jbc.M503640200
DO - 10.1074/jbc.M503640200
M3 - SCORING: Journal article
C2 - 15946934
VL - 280
SP - 28572
EP - 28580
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 31
ER -