MeHG Stimulates Antiapoptotic Signaling in Stem Cells. Annual Report July 1, 2009-June 30, 2010

摘要

In the developing brain, the dominant type of neuronal cell death is apoptosis whereas neurons more frequently die through necrosis in the adult brain. Tightly controlled apoptotic mechanisms are essential for the correct pruning and formation of synaptic connections during development 1; it is thought that these already active death pathways may be responsible for the increased vulnerability of the immature brain to insults 2. The neurons that have failed to establish proper synapses will not survive and will undergo programmed cell death often through apoptosis. The tendency to undergo apoptosis is enhanced because of higher levels of expression of genes that promote apoptosis such as the pro-apoptotic members of the Bcl2 family 3; 4. In the mature brain, a shift in favor of the expression of anti-apoptotic Bcl2 family members occurs. The shift is due, in part, to thyroid hormone signaling. The hairless (Hr) gene (NM-024364) is among one of the most highly thyroid hormone regulated genes in the brain 5. It is found in almost all neurons and in some white matter tracts 6. Hr is also highly expressed in skin epithelial and the hair follicle 7. In Hr knockout mice, a massive disintegration and apoptosis was observed in the bulb of the hair follicle during the first hair cycle in the mouse 7. The higher levels of apoptotic cells in Hr knockouts in the skin suggest that Hr is involved in apoptosis. The objective of the study was to determine the involvement of Hr in apoptosis in the brain. Two in vitro models were used, which were COS cells and mouse embryonic fibroblasts genetically forced to express Hr and cerebellar granule cells from wild-type and Hr knockout mice. Additionally, apoptosis was examined in brains of wild- type and Hr knockout mice.