Biology Reference
In-Depth Information
the presence of an uninterrupted
Hox
gene cluster was previously proposed
to be indispensable for a temporal sequence in AP patterning (
Duboule,
1992
), a relationship that still holds for any animal species displaying such
a developmental strategy.
To understand the underlyingmolecular processes, both temporal and spa-
tial collinearities have been intensively studied at the mouse
HoxD
cluster by
using a combination of genetic and molecular tools (
Tschopp & Duboule,
2011; Tschopp, Tarchini, Spitz, Zakany, & Duboule, 2009
). Interestingly,
internal deletions in the gene cluster affect the outcomes of temporal and spatial
collinearities in different ways. Regarding temporal collinearity, internal dele-
tions generally accelerated the activation of genes located 5
0
to the deletion
breakpoint, whereas in certain instances it delayed the transcriptional activation
of genes located 3 to the breakpoint (
Tschopp et al., 2009
). Therefore,
the timing of gene activation was proposed to rely on a balance between
a3
0
-located positive regulation and a 5
0
-located repressive influence
(
Fig. 4.4
A). In some cases, the separationof the
HoxD
cluster fromits 5
0
-located
flanking sequences accelerated gene expression, further supporting the pres-
ence of repressive elements on this side (
Tschopp & Duboule, 2011
). Impor-
tantly though,
Hoxd
genes were still activated following the correct order,
indicating that additional repressive influences are acting from within
HoxD
cluster to delay the transcription of themost 5
0
-locatedmembers. At later stages
of development, the same internal deletions mostly affected genes located near
the breakpoints, suggesting that local enhancers and silencers contribute to the
maintenance of spatial collinear patterns (
Fig. 4.4
B;
Tschopp et al., 2009
).
In vertebrates,
Hox
genes also function in axial structures other than the
major body axis, where they implement newly acquired collinear transcrip-
tional programs (
Favier & Dolle, 1997; Hombria & Lovegrove, 2003
). The
most thoroughly studied example is that of limb patterning, where analyses
of the mouse
HoxA
and
HoxD
cluster have provided insights into how these
co-opted mechanisms may differ from the original collinear program along
the primary body axis (
Kmita & Duboule, 2003
). Proper patterning of the
mouse limb involves the localized expression of a pair of
Hoxa
genes, as well
as the implementation of two opposite collinear programs at the
HoxD
clus-
ter (
Kmita et al., 2005
; reviewed in
Woltering & Duboule, 2010; Zakany &
Duboule, 2007
).
At early stages of limb budding, a temporal and spatial collinear program
is deployed that resembles in many respects the early collinear mechanisms
implemented along the developing trunk axis. This mostly involves genes
from the central part of the cluster, from
Hoxd8
to
Hoxd11
(
Tarchini &
