Biology Reference
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regulated is usually greater. This difference between limb and brain may be
attributable to the higher proportion of cells initially stimulated to begin
proliferation. Indeed, as examined by
in situ
hybridization in the limb,
TH induces all cell types to upregulate the cell cycle genes, compared to only
the ventricle boundaries in the brain. Comparing tail, brain, and hind limb,
many transcription factors are upregulated in all three tissues, such as KLF9,
c-myc, and NFI-X2. Similarly, chromatin remodelers, such as BAF53,
BAZ1B, CHD4, DNMT1, HDAC1, 2, despite their different fates, are also
commonly upregulated among tissues. In addition, corepressors and
coactivators such as EZH2, HES1, NCoR1, NCoR2, and TRIP3 are also
commonly upregulated among tissues. Nevertheless, although there are
many genes similarly regulated in all three programs (tail, limb, and brain),
the tail (death) program is very different from the limb and brain (growth)
programs. In order to identify candidate genes that may determine tissue-
specific T3-responses,
Das et al. (2006)
identified 36 differentially regulated
genes from the hind limb that regulate transcription at the earliest time point
studied, that is, 14 h of TH treatment. Several of these genes are upregulated
in the limb and brain but not in the tail and might control the opposite ex-
pression patterns in these two programs, including CEBPD, HBP1,
HDAC9, HES1, MYOD1, TRMM55, and ZFP36. In addition to differen-
tially expressed transcriptional regulators and chromatin modifiers, different
preexisting chromatin states and presence of tissue-specific coactivators and/
or corepressors likely interact with TH-response genes in a tissue-specific
manner to explain different gene regulation cascades among tissues.
Downstream of the TH-induced gene regulation cascade, genes in sev-
eral key functional categories are regulated in the opposite manner in tail
versus limb programs. Many of the genes that encode energy pathway pro-
teins that are localized in the mitochondria (e.g., the genes in the mitochon-
drial electron transport chain) are downregulated in tail muscle but
upregulated during limb growth. Also, 8 out of 17 genes encoding tricar-
boxylic acid cycle enzymes are upregulated in the limb and 6 of these are
downregulated in the tail. Additionally, half of the 32 genes in the
cytoplasm-localized glycolytic pathway are downregulated in tails at meta-
morphic climax, and four of those are upregulated in the limb.
In a clever use of microarray analysis, Brown and colleagues investigated
the developmental basis of a limb muscle-wasting phenotype (
Cai, Das, &
Brown, 2007
). When a dominant negative version of the TH receptor
(TRDN) was inducibly expressed in limb muscle cells in transgenic frogs
undergoing metamorphosis, limb muscle fibers disintegrated but the muscle
