Biology Reference
In-Depth Information
In Drosophila and in mouse, each Hox gene has been knocked out and a
detailed understanding of their functions is emerging (Reviewed in
McGinnis and Krumlauf, 1992 ; Wellik, 2009 ). In flies, loss-of-function
mutations cause homeotic transformations, in which segmental identities
are transformed to those of other (usually more anterior) segments. In
vertebrates, homeotic transformations are also observed although pheno-
types are not always straightforward to interpret in these terms. Individual
Hox mutations often do not result in widespread defects; however, para-
logous gene knockouts are uncovering redundant but dramatic patterning
functions of related genes ( Horan et al ., 1995 ; McIntyre et al ., 2007 ; Wellik
and Capecchi, 2003 ; reviewed comprehensively in Wellik, 2007 ). With this
accumulating knowledge of Hox function, a key outstanding question in
the field is how Hox gene expression is so exquisitely regulated.
Precise spatial and temporal Hox expression is governed by multiple
mechanisms and is best studied in Drosophila and mouse. Individual (some-
times multiple) promoters and enhancers exist for most Hox genes, but in
vertebrates, there are also cases of enhancer and even promoter sharing to
produce polycistronic transcripts. Individual enhancers often exhibit both
auto- and cross-regulation by Hox proteins. Promoter competition also
occurs in both vertebrates and invertebrates. (e.g., see Coulombe et al .,
2010 ; Gould et al ., 1997 ; Herault et al ., 1997 ; Ohtsuki et al ., 1998 ; Sharpe
et al ., 1998 ). At least in vertebrates, in which clusters are more consolidated
than in other lineages ( Duboule, 2007 ), global enhancer elements have been
found that regulate collinear expression along the body axis or nested 5 0 Hoxd
expression in appendages (reviewed in Deschamps, 2007 ). Long noncoding
RNAs within or near clusters can regulate Hox transcription in cis , for
example, via transcriptional interference in the Drosophila bithorax complex,
or in trans , for example, through effects on chromatin packaging, in verte-
brates ( Rinn et al ., 2007 ; Wang et al ., 2011 ; reviewed in Brock et al ., 2009 ).
Collinear expression is found even in species where Hox clusters are dis-
persed and thus in those cases must depend on individual enhancer elements.
Nevertheless, both global regulatory elements and extensive cross-regulation
of individual Hox enhancers and promoters are often cited as reasons for the
maintenance of Hox clustering in most bilaterian lineages.
Extensive posttranscriptional regulation also ensures proper Hox expres-
sion, evidenced by several cases where Hox protein and mRNA expression
patterns are strikingly different ( Brend et al ., 2003 ; Nelson et al ., 1996 ).
Novel mechanisms of posttranscriptional regulation are continually being
uncovered ( Kondrashov et al ., 2011 ), and in recent years, it has become
clear that one important mechanism is via microRNA (miRNA) control,
and in particular, via miRNA genes embedded within the Hox clusters.
miRNAs are short, approximately 22-nucleotide (nt) RNA species
that act posttranscriptionally to negatively regulate gene expression
(reviewed in Bartel, 2009 ). Nascent primary transcripts undergo a series
Search WWH ::




Custom Search