Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate.
Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion. Mouse mutations in Fmn1 cause aberrant fusion of carpal digits. We report here that FlnB and Fmn1 physically interact, are co-expressed in chondrocytes in the growth plate and share overlapping expression in the cell cytoplasm and nucleus. Loss of FlnB leads to a dramatic decrease in Fmn1 expression at the hypertrophic-to-ossification border. Loss of Fmn1-FlnB in mice leads to a more severe reduction in body size, weight and growth plate length, than observed in mice following knockout of either gene alone. Shortening of the long bone is associated with a decrease in chondrocyte proliferation and an overall delay in ossification in the double-knockout mice. In contrast to FlnB null, Fmn1 loss results in a decrease in the width of the prehypertrophic zone. Loss of both proteins, however, causes an overall decrease in the width of the proliferation zone and an increase in the differentiated hypertrophic zone. The current findings suggest that Fmn1 and FlnB have shared and independent functions. FlnB loss promotes prehypertrophic differentiation whereas Fmn1 leads to a delay. Both proteins, however, regulate chondrocyte proliferation, and FlnB may regulate Fmn1 function at the hypertrophic-to-ossification border, thereby explaining the overall delay in ossification.
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Jianjun
J
Hu
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Jie
J
Lu
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Gewei
G
Lian
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
Russell J
RJ
Ferland
CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Markus
M
Dettenhofer
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA vsheen@bidmc.harvard.edu.
Volney L
VL
Sheen
D000818:Animals; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology*; D005326:Fetal Proteins / Q000172:deficiency / Q000378:metabolism*; D064448:Filamins / Q000172:deficiency / Q000378:metabolism*; D000080865:Formins; D006132:Growth Plate / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D006984:Hypertrophy; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism
D005326:Fetal Proteins; D064448:Filamins; D000080865:Formins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D044168:Receptor, Parathyroid Hormone, Type 1