International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


I31. The Role of Presenilin-1 during Neurogenesis and Somitogenesis

Ken-ichi Koizumi1, Shigeki Yuasa2 and Haruhiko Koseki1,
1
Department of Molecular Embryology and
2
Department of Anatomy, Graduate School of Medicine, Chiba University

Mutations in presenilin-1 (PS-1) gene are linked to early onset familial Alzheimer's disease. To understand the physiological function of PS-1 on the neural development, we generated mice with a targeted null mutation in the murine PS-1 alleles. As no alive PS-1-deficient mice were found, brains from embryonic mice were used for experiments. Western blot analysis revealed that Notch-1 failed to be processed to an active form, Notch intracellular domain (NICD), in PS-1-deficient embryonic brains. Junctional structures such as zonulae adhaerentes were defective in the ventricular zone of PS-1-deficient neocortex. In the corresponding regions of PS-1-deficient neocortex, b-catenin expression was down-regulated at the protein level, and aberrantly scattered. Bromodeoxyuridine (BrdU) labeling experiments revealed that S-phase neuronal precursor cells in the ventricular zone of PS-1-deficient embryos were abnormally localized in the lower layer. An immunohistochemical analysis revealed that the expression of class III b-tubulin, a differentiation marker for the early postmitotic neurons, was upregulated throughout the neocortex of PS-1-deficient embryos, especially in the ventricular surface. These results suggest that PS-1 regulates neurogenesis in the ventricular zone, presumably via the Notch-1 processing.

Segmentation of the somitic mesoderm was also impaired in PS-1 mutants. Establishment of caudal half somite was totally affected. Interestingly, cyclic expression of l-fringe and Mesp2 were still retained in PS-1 mutant but the amount of l-fringe and Mesp2 transcripts were significantly reduced. This implies that PS-1 is required for the autoregulation of l-fringe function during somitogenesis.


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