Functional analyses of neural development genes

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This project aims to clarify the molecular mechanism that regulates neural development. For this purpose, we characterized the SulfFP1, SulfFP2, and Autotaxin genes that we have previously identified as floor plate specific genes. We summarize our findings as follows. SulfFP is a novel member of the sulfatase family, it is secreted into culture medium when transfected, it is cleaved in furin-dependent and independent manners, it has endosulfatase activity that hydrolyses 6-0-sulfate in the glucosamine residues in intact heparin and heparan sulfate, trisulfated disaccharide units becomes a good substrate for SulfFPs, and its activity is high at neutral pH rather than acidic pH. Autotaxin is a secreted protein that was identified as a chemotaxis-promoting factor. The presence of a phosphodiesterase domain predicted the role of Autotaxin in the nucleotide metabolism in the extracellular space. Recent studies, however, revealed that Autotaxin has a lysophospholipase D activity that generat … More es lysophosphatidic acid (LPA) and sphingosine-1-phosphate (SIP).Although many lines of in vitro studies have provided ample evidence suggesting their functions, their physiological roles in vivo remain unknown. Therefore, we have generated the knockout mice for these genes and analyzed their phenotypes. The mice deficient for either SulfFP1 or SulfFP2 genes appear to be normal, suggesting the functional redundancy of these genes. Indeed our previous studies showed that SulfFP1 and SulfFP2 expressions are largely overlapping in mouse embryos. In contrast, many of the mice deficient for both SulfFP1 and SulfFP2 genes die within 1 day after birth for unknown reason. The double-knockout mice showed abnormality in the nervous system and growth retardation. Autotaxin-deficient mice die at embryonic day 8~9, and some mice showed excencephaly phenotype, indicating the importance of Autotaxin in neural development. Conditional knockout mice that have defect only in the nervous system are necessary to investigate the role of Autotaxin in late neural development. Less