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Fig. 6. HDAC inhibition phenocopies ARNT deletion with respect to HIF1 target gene
expression and TS cell differentiation. (A) Undifferentiated wild-type TS
cells were cultured with (+) or without (–) 100 nM trichostatin A (TSA)
or 100 nM geldanamycin A (GA). Then Pgk1 gene expression was analyzed
by northern blot hybridization. Both compounds significantly reduced
Pgk1 mRNA levels, but to a lesser extent than ARNT deletion. (B)
Wild-type TS cells were differentiated in the presence or absence of TSA or GA
and the expression of mRNAs encoding lineage-markers was analyzed by northern
blot hybridization. Both compounds inhibited Pl-I expression, suggesting
impaired trophoblast giant cell differentiation. Interestingly, TSA but not
GA, inhibited 4311 expression, suggesting differential effects of these
compounds on spongiotrophoblast differentiation. Enhanced expression of Tfeb
suggested that TS cell differentiation was redirected to chorionic trophoblast
formation. (C) Phase-contrast microscopy of differentiated wild-type TS cells
cultured with or without 100 nM TSA for the duration of the differentiation
period. Although many large trophoblast giant cells and clusters of
spongiotrophoblasts were seen in untreated cultures, TSA treatment promoted
syncytialization (broken circles indicated by arrows) along with cytoplasmic
vacuolization and membrane breakdown (arrowheads) as seen with differentiating
Arnt-null cells.
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