Altered growth characteristics of skin fibroblasts from wild-derived mice, and genetic loci regulating fibroblast clone size.
Mouse fibroblast senescence in vitro is an important model for the study of aging at cellular level. However, common laboratory mouse strains may have lost some important allele variations related to aging processes. In this study, growth in vitro of tail skin fibroblasts (TSFs) derived from a wild-derived stock, Pohnpei (Pohn) mice, differed from growth of control C57BL/6 J (B6) TSFs. Pohn TSFs exhibited higher proliferative ability, fewer apoptotic cells, decreased expression of Cip1, smaller surface areas, fewer cells positive for senescence associated-beta-galactosidase (SA-beta-gal) and greater resistance to H(2)O(2)-induced SA-beta-gal staining and Cip1 expression. These data suggest that TSFs from Pohn mice resist cellular senescence-like changes. Using large clone ratio (LCR) as the phenotype, a quantitative trait locus (QTL) analysis in a Pohn/B6 backcross population found four QTLs for LCR: Fcs1 on Chr 3 at 55 CM; Fcs2 on Chr X at 50 CM; Fcs3 on Chr 4 at 51 CM and Fcs4 on Chr 10 at 25 CM. Together, these four QTLs explain 26.1% of the variations in LCRs in the N2 population. These are the first QTLs reported that regulate fibroblast growth. Glutathione S transferase mu (GST-mu) genes are overrepresented in the 95% confidence interval of Fcs1, and Pohn TSFs have higher H(2)O(2)-induced GST-mu 4, 5 and 7 mRNA levels than B6 TSFs. These enzymes may protect Pohn TSFs from oxidation.
Yuan
Rong
R
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Flurkey
Kevin
K
Van Aelst-Bouma
Renee
R
Zhang
Weidong
W
King
Benjamin
B
Austad
Steve
S
Miller
Richard A
RA
Harrison
David E
DE
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D048429:Cell Size; D016922:Cellular Senescence / Q000187:drug effects; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D012867:Skin / Q000166:cytology*; D013623:Tail / Q000166:cytology / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D005982:Glutathione Transferase