| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
SEZ-12 is a seizure-related mouse cDNA whose expression level is down-regulated by a convulsant drug, pentylenetetrazol, both in cultured cerebral neurons and in adult brain. Sequence analysis of SEZ-12 shows a significant homology to a human cDNA, named DGCR2/IDD/LAN, isolated from the chromosome 22q11.2 region critical for the DiGeorge syndrome. Here we determined the chromosomal localization of SEZ-12 gene, Sez12, by interspecific backcross analysis. Sez12 mapped on the proximal region of mouse chromosome 16 homologous to the human chromosome 22q11. RNA blotting and whole mount in situ hybridization of Sez12 mRNA showed a relative abundance in craniofacial region during mouse embryogenesis. To further determine the molecular mechanism underlying this expression, the deletion constructs of the Sez12 promoter were transfected into NIH3T3 cells. The results revealed an essential domain (-180 to -1) which included a cis-acting element for the transcription factor c-Ets1 and was upregulated its transcriptional activity by retinoic acid. Moreover, we showed that Sez12 products expressed in Xenopus oocytes were induced a large inward current by extracellular application of an oligosaccharide ligand, ganglioside glycolipid, suggesting that the Sez12 protein is a key effector whose interaction with some cell-surface ligands result in normal cellular development during embryogenesis. Taken together, Sez12 may play an important role in craniofacial development and that haploinsufficiency of this human homologue may be related in part to pathogenesis of DiGeorge syndrome. Now, to directly understand the physiological role of Sez12 in the animal, a null mutation has been introduced into the gene by homologous recombination in mouse embryonic stem cells.
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