odd-paired
opa is positively regulated by Antennapedia and abdominal-A at the location of the first and third visceral mesodermal midgut constrictions respectively. Between these domains opa is negatively regulated by Ultrabithorax and decapentaplegic (Cimbora, 1995).
Hox genes have large expression domains, yet these genes control the formation of fine pattern elements at specific locations. The mechanism underlying subdivision of the abdominal-A (abdA) Hox domain in the visceral mesoderm has been examined. AbdA directs formation of an embryonic midgut constriction at a precise location within the broad and uniform abdA expression domain. The constriction divides the abdA domain of the midgut into two chambers, the anterior one producing the Pointed (Pnt) ETS transcription factors and the posterior one the Odd-paired (Opa) zinc finger protein. Transcription of both pnt and opa is activated by abdA. Near the anterior limit of the abdA domain, two signals, Decapentaplegic and Wingless, are produced, in adjacent non-overlapping patterns, under Hox control in mesoderm cells.
AbdA is proposed to activate three targets, in distinct subsets of its broad domain of expression: wg at the anterior boundary of Connectin (Con) patch 7; pnt from anterior Con patch 7 to anterior Con patch 8, and opa, from anterior Con patch 8 through Con patch 11. Dpp signaling plays a central role in setting these distinct expression domains. The initial activation of wg by AbdA requires dpp. opa is activated in all abdA-expressing cells that do not receive a Dpp signal, defining the site of the posterior constriction. wg, in collaboration with abdA, activates pnt to generate the appropriate number of cells in the third midgut chamber, positioning the posterior constriction at the proper distance from the central constriction and partitioning the posterior midgut appropriately. Fine patterning of the posterior midgut is achieved by the activity of diffusible signals emanating from the central midgut, a remarkably long-range organizing effect (Bilder, 1998).
Hox proteins play fundamental roles in generating pattern diversity during development and evolution, acting in broad domains but controlling localized cell diversification and pattern. Much remains to be learned about how Hox selector proteins generate cell-type diversity. In this study, regulatory specificity was investigated by dissecting the genetic and molecular requirements that allow the Hox protein Abdominal A to activate wingless in only a few cells of its broad expression domain in the Drosophila visceral mesoderm. The Dpp/Tgfß signal controls Abdominal A function, and Hox protein and signal-activated regulators converge on a wingless enhancer. The signal, acting through Mad and Creb, provides spatial information that subdivides the domain of Abdominal A function through direct combinatorial action, conferring specificity and diversity upon Abdominal A activity (Grienenberger, 2003).
This study provides a conceptual framework for understanding the molecular basis of regional Hox protein transcriptional activity. Dpp and Wg signaling subdivide the AbdA Hox domain, allowing activation of pointed (pnt) and opa target genes in the third and fourth midgut chambers, respectively. Based upon the data presented here, it is suspected that the localized activation of pnt and opa by AbdA also relies on direct enhancer integration of Hox and signaling inputs. Accordingly, a Hox/signaling combinatorial code functionally subdivides the domain where a single Hox protein is made, giving rise to discrete patterns of target gene activation. The structures of relevant cis-regulatory regions of AbdA target genes are instrumental for determining which signal is required to allow activation by AbdA. The pnt midgut enhancer would contain AbdA and Wg response elements and would be activated by AbdA specifically in the third midgut chamber through the combinatorial action of AbdA and the Drosophila Tcf/Arm transcriptional effector of Wg signaling. Similarly, the opa midgut enhancer would contain AbdA and Dpp response elements and would be activated only in the fourth gut chamber by AbdA, in this case because of an inhibitory effect of the Dpp-regulated transcription factor on AbdA activity (Grienenberger, 2003).
There are several distinct phases of runt expression in the early embryo. Each phase depends on a different set of regulators. In a third distinct phase of expression, at the onset of gastrulation, runt becomes
expressed in 14 stripes. fushi tarazu plays a negative regulatory role in generating this pattern,
whereas the pair-rule genes paired and odd-paired are required for activating or maintaining runt expression during these stages (Klingler, 1993).
The odd-paired gene is essential for parasegmental subdivision of the Drosophila
embryo. opa is required for the activation of wingless and engrailed in all parasegments.
OPA does not act in a spatially restricted manner to establish the position of en and wg expression. Because of its ubiquitous expression, OPA must cooperate with other spatially restricted proteins to achieve proper pair-rule subdivision of
the Drosophila embryo (Benedyk, 1994).
The exact positioning of neuroblasts in the neuroectodermal region that gives rise to the CNS is regulated by a combination of pair-rule genes. Proneural achaete-scute genes are controlled by combinations of axis-patterning genes through a common intergenic control region. Specifically, in every segment, the loss of odd-paired function removes achaete expression from the second row of clusters in each segment (Skeath, 1992).
opa regulates bagpipe in the visceral mesoderm (Cimbora, 1995).
Acting either via opa or in concert with it, Tenascin major, the extracellular protein related to vertebrate tenascin, initiates a signal transduction cascade which acts on downstream
targets such as paired, sloppy-paired, gooseberry, engrailed and wingless, leading to an opa-like phenotype (Baumgartner, 1994).
DPTP61F is a non-receptor protein tyrosine phosphatase that is expressed during Drosophila oogenesis and embryogenesis. DPTP61F transcripts are alternatively
spliced to produce two isoforms of the protein which are targeted to different
subcellular locations. The transcript encoding DPTP61Fm accumulates in 16
segmentally repeated stripes in the ectoderm during germband extension. These
stripes are flanked by, and adjacent to, the domains of engrailed and wingless gene
expression along the anterior/posterior axis. In stage 10 embryos, the domains of
DPTP61Fm transcript accumulation are wedge shaped and roughly coincide with the
area lateral to the denticle belts that will give rise to naked cuticle. The DPTP61Fm
transcript is also expressed later in embryogenesis in the central nervous system. The
segmental modulation of DPTP61Fm transcript accumulation along the A/P axis of the
germband is regulated by the pair-rule genes, and the intrasegmental pattern of
transcript accumulation is regulated by the segment polarity genes. In hairy mutants, the complement of DPTP62Fm stripes is reduced by half, to approximately eight wide stripes. It is presumed that odd numbered stripes have been deleted. Within embryos homozygous for a strong eve allele, odd stripes are absent except for stripe 1. In odd paired mutants every even stripe is decreased. In paired mutants odd numbered domains of expression are shifted anteriorly towards the even numbered domains. wingless, hedgehog, naked and patched are involved in refining the pattern of mRNA accumulation within each parasegment (Ursuliak, 1997).
The eye/antennal discs of Drosophila form most of the adult head
capsule. The role of the BMP family member
decapentaplegic (dpp) in the process of head formation is being analyzed, since a class of cis-regulatory dpp mutations
(dpps-hc) have been identified that specifically disrupts expression in the lateral peripodial epithelium of eye/antennal discs and is required for
ventral head formation. This study describes the recovery of mutations in
odd-paired (opa), a zinc finger transcription factor related
to the vertebrate Zic family, as dominant enhancers of this dpp head
mutation. A single loss-of-function opa allele in combination with a
single copy of a dpps-hc produces defects in the ventral
adult head. Furthermore, postembryonic loss of opa expression alone
causes head defects identical to loss of dpps-hc/dpps-hc, and dpphc/+;opa/+ mutant combinations. opa
is required for dpp expression in the lateral peripodial epithelium,
but not other areas of the eye/antennal disc. Thus a pathway that includes
opa and dpp expression in the peripodial epithelium is
crucial to the formation of the ventral adult head. Zic proteins and members
of the BMP pathway are crucial for vertebrate head development, since mutations
in them are associated with midline defects of the head. The interaction of
these genes in the morphogenesis of the fruitfly head suggests that the
regulation of head formation may be conserved across metazoans (Lee, 2007).
This work demonstrates that opa is an upstream activator of
dpp in the peripodial epithelium, and acts in a cell-autonomous
fashion. It is not known whether this role is direct, with Opa acting as a
transcription factor for dpp, or through other proteins. This ability
to activate dpp appears limited to the peripodial epithelium of the
eye/antennal disc, since misexpression of Opa in the disc proper does not induce
expression. Furthermore, Opa acts only on a dpp reporter that has
expression restricted to the peripodial epithelium of the eye/antennal disc.
With the exception of antennal defects, loss-of-function clones of
opa produce identical head defects to homozygous
dpps-hc mutants, and ectopic expression of either Dpp or
Opa in the peripodial epithelium produces a similar spectrum of misplaced
sensory structures. These data suggest that dpp is the major target
of opa in the peripodial epithelium (Lee, 2007).
Both opa and dpp are involved in embryonic midgut
development, where dpp is a negative regulator of opa in the
visceral mesoderm. In addition, BMP2 and BMP4 are negative regulators of Zic
proteins in zebrafish, but the exact mechanism of this regulation is unclear.
Thus, Zic family proteins are often seen in regulatory networks with BMP
proteins, but there does not seem to be a canonical regulatory relationship.
These data indicates that during eye/antennal disc development opa
exerts a positive effect on peripodial dpp (Lee, 2007).
Both opa and dpp exert their role on ventral head
development through expression limited to the peripodial epithelium of the
eye/antennal disc. The structures affected in ventral head capsule mutations,
such as palps and vibrissae, are reported to arise from the disc proper in the
fate map of the eye/antennal disc; thus the effect of Opa-Dpp signal transduction
could be to cross epithelial layers, from the peripodial epithelium to the
disc proper. Loss of lateral peripodial Dpp expression
results in apoptosis in the underlying disc proper, which
further suggests a role for peripodial signaling to support disc proper cell
viability and morphogenesis. However, when the descendants of peripodial cells
are followed by the perdurance of ß-galactosidase expression through
metamorphosis, significant contributions of lateral peripodial cells are found
in areas of the ventral head where defects are observed in
dpps-hc or opa mutations, suggesting that the
ventral adult head is formed from descendants of both disc proper and
peripodial cells. Adult head expression has also been seen with the
MS1096-Gal4 driver, of which expression in the eye disc is limited to
the lateral and medial peripodial epithelium and margin cells.
These data provide further support to the idea that the peripodial epithelium
provides more than passive or purely mechanical functions during disc
development. The role of the peripodial epithelium in imaginal disc
development has begun to receive more attention, and there is evidence that
peripodial-specific signaling affects the patterning of the eye, growth
control and the fusion of discs at metamorphosis. It now seems likely that in addition to providing such support to cells of the disc proper, peripodial cells contribute directly to the cuticle of the adult head (Lee, 2007).
In mice and humans, Zic genes are associated with holoprosencephaly, a
congenital head defect the extreme manifestation of which is cyclopia. In
holoprosencephaly there is variable loss or disruption in the development of
the ventral forebrain, and midline facial structures.
Holoprosencephaly is a common defect in humans, and genes in the TGF-ß
and hedgehog pathways are also associated with both the human and mouse
condition. Relevant to this work, a significant number of
holoprosencephaly cases result from autosomal dominant inheritance, and often,
obligate carriers of these autosomal dominant pedigrees are clinically normal. This
incomplete penetrance suggests extreme dose sensitivity and the presence of
multiple modifying loci. The ability of a genetic screen to recover multiple
dominant enhancers of the dpp ventral head defect, including
opa, suggests that this may be a model for the kind of digenic
inheritance seen with holoprosencephaly. The hedgehog pathway is known to be
crucial to adult head development in Drosophila, and this work adds TGF-ß and opa to this process in the fruitfly. It will be of interest to see how many other connections exist between vertebrate and fly head malformations (Lee, 2007).
Home page: The Interactive Fly © 1997 Thomas B. Brody, Ph.D.
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