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Abstract
Growth and differentiation factor Associated Serum Protein (GASP) 1 and 2 are proteins known to be involved in the control of myostatin activity at least in vitro. Most deuterostome GASPs share a modular organization including WAP, follistatin/kazal, IGc2, two kunitz, and NTR domains. Based on an exon shuffling model, we performed independent phylogenetic analyses on these modules and assessed that papilin is probably a sister sequence to GASP with a divergence date estimated from the last common ancestor to bilateria. The final organization was acquired by the addition of the FS domain in early deuterostomes. Our study revealed that Gasp genes diverged during the first round of genome duplication in early vertebrates. By evaluating the substitution rate at different sites on the proteins, we showed a better conservation of the follistatin/kazal domain of GASP1 than GASP2 in mammals, suggesting a stronger interaction with myostatin. We also observed a progressive increase in the conservation of follistatin and kunitz domains from the ancestor of Ciona to early vertebrates. In situ hybridization performed on mouse embryos showed a weak Gasp1 expression in the formed somites at 10.5 dpc and in limb buds from embryonic E10.0 to E12.5. Similar results were obtained for zebrafish embryos. We propose a synthetic view showing possible interactions between GASP1 and myostatin and highlighting the role of the second kunitz domain in preventing myostatin proteolysis.
Highlights
GASP1 ( = WFIKKN2) and GASP2 ( = WFIKKN1), are two highly similar multi-domain secreted proteins including several modules retrieved in protease-inhibitory proteins: a signal peptide, a whey acidic protein domain (WAP), a follistatin/kazal domain, an immunoglobulin domain, two tandem kunitz modules and a NTR domain [1], [2]
In vitro experiments [4] showed that these two proteins have a high affinity for two TGF beta family members encoded by paralogous genes and implicated in musculoskeletal development: myostatin known as GDF8, a protein playing an inhibitory role in prenatal and postnatal muscle development, and bone morphogenic protein 11 called GDF11 which is implicated in axial skeleton formation during embryogenesis [5], [6]
To get insight into the events separating sequences included in primitive metazoans and deuterostome Growth and differentiation factor Associated Serum Protein (GASP), we studied the phylogeny of each module separately (WAP, kazal, IGc2, and both kunitz)
Summary
GASP proteins can bind to the myostatin propeptide, implicated in GDF8 inhibition by protein-protein interaction, due to their NTR domain hypothetical fixation [2], [4]. Haidet et al [8] observed a significant increase in skeletal muscle mass and strength in mice after cytomegalovirus-Gasp1-AAV1 (Adeno-associated virus 1) muscle injection Taken together, these results suggest the implication of GASP proteins in the regulation of muscle mass in a myostatin dependent manner. Gasp is expressed in ovary, testis, pancreas, brain, lung, and Gasp in pancreas, thymus, liver, kidney, lung, testis and inner ear [1], [4], [9] These expression patterns argue for physiological roles independent of interactions with GDF8 and GDF11. Supporting that view, it has been recently shown that both GASP proteins can bind to TGF beta, BMP2 and BMP4 but do not inhibit their activity in vitro [10]
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