Developmental and functional significance of the CSF-1 proteoglycan chondroitin sulfate chain.
The primary macrophage growth factor, colony-stimulating factor-1 (CSF-1), is homodimeric and exists in 3 biologically active isoforms: a membrane-spanning, cell-surface glycoprotein (csCSF-1) and secreted glycoprotein (sgCSF-1) and proteoglycan (spCSF-1) isoforms. To investigate the in vivo role of the chondroitin sulfate glycosaminoglycan (GAG) chain of spCSF-1, we created mice that exclusively express, in a normal tissue-specific and developmental manner, either the secreted precursor of spCSF-1 or the corresponding precursor in which the GAG addition site was mutated. The reproductive, hematopoietic tooth eruption and tissue macrophage defects of CSF-1-deficient, osteopetrotic Csf1(op)/Csf1(op) mice were corrected by transgenic expression of the precursors of either sgCSF-1 or spCSF-1. Furthermore, in contrast to the transgene encoding csCSF-1, both failed to completely correct growth retardation, suggesting a role for csCSF-1 in the regulation of body weight. However, spCSF-1, in contrast to sgCSF-1, completely resolved the osteopetrotic phenotype. Furthermore, in transgenic lines expressing different concentrations of sgCSF-1 or spCSF-1, spCSF-1 more efficiently corrected Csf1(op)/Csf1(op) defects of tooth eruption, eyelid opening, macrophage morphology, and B-cell deficiency than sgCSF-1. These results indicate an important role of the CSF-1 chondroitin sulfate proteoglycan in in vivo signaling by secreted CSF-1.
Nandi
Sayan
S
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
Akhter
Mohammed P
MP
Seifert
Mark F
MF
Dai
Xu-Ming
XM
Stanley
E Richard
ER
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001862:Bone Resorption / Q000235:genetics; D002809:Chondroitin Sulfates / Q000378:metabolism*; D005143:Eyelids / Q000033:anatomy & histology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006130:Growth Disorders / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009805:Odontogenesis / Q000235:genetics; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012098:Reproduction / Q000235:genetics; D014078:Tooth Eruption / Q000235:genetics
C038142:chondroitin sulfate glycosaminoglycan; D016173:Macrophage Colony-Stimulating Factor; D002809:Chondroitin Sulfates