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Another example of how this approach can be used to determine the relationships
of interacting gene networks involves work on the PAR proteins, which play crucial
roles in establishing the anterior-posterior axis of embryos after fertilization
(
Munro et al., 2004
). The hierarchical relationships between PAR proteins are
highly spatially dependent. The PAR-3 protein is normally polarized in the anterior
of embryos, whereas the PAR-2 protein is enriched in the posterior. In par-2
mutants, PAR-3 is mislocalized to the posterior, which suggests that PAR-2
excludes PAR-3 from the posterior. This indicates that par-2 may function upstream
of par-3 in the posterior. Conversely, in the anterior of the embryo, par-3 is
upstream of par-2 because in par-3 mutants PAR-2 is aberrantly accumulated in
the anterior. In cases like cell polarity, careful localization dependency analysis is
crucial in resolving the dynamic relationship between gene products in controlling
a biological process.
E. Gene Expression Dependency for Gene Ordering
Many pathways and networks that control developmental events, such as cell-fate
specification (
Chang et al., 2004
), aging (
Lin et al., 2001
), and developmental
timing regulation (
Lee et al., 1993; Reinhart et al., 2000
), often involve transcrip-
tion factors and/or components subject to post-transcriptional regulation. In these
pathways and networks, interactions between two components are sometimes man-
ifested by one component regulating expression of another. The hierarchical rela-
tionship among these components can be determined by their gene expression
dependency. To determine this dependency expression of a full-length GFP reporter
transgene carrying one gene (gene A) under control of its endogenous promoter is
often examined in the mutant background of the other (gene B). In the case where
expression of gene A is reduced in the mutant background of gene B, it suggests that
gene B likely acts upstream of gene A as a positive regulator. For example, using
this strategy,
Johnston and Hobert (2003)
placed a microRNA gene, lsy-6,intoa
transcriptional cascade of three homeobox transcription factors (ceh-36, lim-6,and
cog-1) that regulate left-right functional asymmetrical expression of a guanyl
cyclase (gcy) chemoreceptor gene, gcy-5, in ASE left (ASEL) neuron, but not in
ASE right (ASER) neuron (
Chang et al., 2003
)(
Fig. 10
). To order lsy-6 into this
regulatory hierarchy, they analyzed the expression of the transcription factors
ceh-36, lim-6,andcog-1 in a lsy-6 mutant background. Expression of ceh-36 gene
was unaffected, but expression of the normally left-expressed lim-6 gene was lost,
suggesting that lsy-6 acted upstream of lim-6 in ASEL. Conversely, expression of
cog-1, a negative regulator of lim-6, was upregulated in ASEL, indicating that lsy-6
acted upstream of cog-1 as a negative regulator. Consistent with this notion, the
removal of cog-1 activity in a lsy-6 mutant background resulted in upregulation of
lim-6
expression, suggesting that
lsy-6
acts through
cog-1
to regulate
lim-6
expression.
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