Abstract
BackgroundCell surface heparan sulfate proteoglycans (HSPGs) act as co-receptors for multiple families of growth factors that regulate animal cell proliferation, differentiation and patterning. Elimination of heparan sulfate during brain development is known to produce severe structural abnormalities. Here we investigate the developmental role played by one particular HSPG, glypican-1 (Gpc1), which is especially abundant on neuronal cell membranes, and is the major HSPG of the adult rodent brain.ResultsMice with a null mutation in Gpc1 were generated and found to be viable and fertile. The major phenotype associated with Gpc1 loss is a highly significant reduction in brain size, with only subtle effects on brain patterning (confined to the anterior cerebellum). The brain size difference emerges very early during neurogenesis (between embryonic days 8.5 and 9.5), and remains roughly constant throughout development and adulthood. By examining markers of different signaling pathways, and the differentiation behaviors of cells in the early embryonic brain, we infer that Gpc1-/- phenotypes most likely result from a transient reduction in fibroblast growth factor (FGF) signaling. Through the analysis of compound mutants, we provide strong evidence that Fgf17 is the FGF family member through which Gpc1 controls brain size.ConclusionThese data add to a growing literature that implicates the glypican family of HSPGs in organ size control. They also argue that, among heparan sulfate-dependent signaling molecules, FGFs are disproportionately sensitive to loss of HSPGs. Finally, because heterozygous Gpc1 mutant mice were found to have brain sizes half-way between homozygous and wild type, the data imply that endogenous HSPG levels quantitatively control growth factor signaling, a finding that is both novel and relevant to the general question of how the activities of co-receptors are exploited during development.
Highlights
Cell surface heparan sulfate proteoglycans (HSPGs) act as co-receptors for multiple families of growth factors that regulate animal cell proliferation, differentiation and patterning
Generation of glypican-1 null mice Homologous recombination was used in embryonic stem (ES) cells to flank the first exon of Gpc1 - which includes the translational start site and signal sequence - with loxP sites, and successfully targeted cells were transiently transfected with Cre recombinase to induce excision (Figure 1A)
Cell-surface HSPGs are critical for growth and patterning in numerous tissues and organ systems, presumably as a consequence of their actions as growth factor co-receptors
Summary
Cell surface heparan sulfate proteoglycans (HSPGs) act as co-receptors for multiple families of growth factors that regulate animal cell proliferation, differentiation and patterning. The elimination of the individual core proteins that carry cell surface heparan sulfate generally produces more subtle or tissue-restricted defects, in mammals [8,9,10,11,12,13,14,15,16] Most likely this reflects the relatively large number of cell surface HSPGs (six glypicans and four syndecans in mammals), their overlapping patterns of expression, and a likelihood of functional redundancy that is made high by the fact that carbohydrate moieties mediate much of their function. The analysis of core protein mutants has provided novel insights into at least some of the developmental and physiological processes in which HSPGs participate
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