1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
02142, USA
Author for correspondence (e-mail:
rebay{at}wi.mit.edu)
SUMMARY
Context-specific integration of information received from the Notch, Transforming growth factor ß, Wingless/Wnt, Hedgehog and Epidermal growth factor receptor signaling pathways sets the stage for deployment of the retinal determination gene network (RDGN), a group of transcription factors that collectively directs the formation of the eye and other tissues. Recent investigations have revealed how these transcription factors are regulated by their interactions with each other and with effectors of the above signaling pathways. Further study of the RDGN may provide insights into how common cues can generate context-specific responses, a key aspect of developmental regulation that remains poorly understood.
Introduction
Eye development in different organisms produces strikingly different structures: the primitive eye of planaria, the compound eye of insects, and the camera-like eye of vertebrates. Although these visual organs are morphologically distinct, the molecular mechanisms that underlie their development are remarkably conserved. The specification of the eye field in these diverse organisms requires the expression of homologous members of the retinal determination gene network (RDGN), a group of transcription factors and cofactors. Recent studies have explored a role for the RDGN as an interface for the integration of multiple signaling pathways, a function that is crucial for the proper development of many tissues, including the eye, gonad, muscle and ear. Together, these analyses indicate that this network affects, and is affected by, multiple signaling pathways in a context-specific manner. As such, studies that probe this specificity may provide a means to understanding the mechanisms that underlie specific responses to developmental regulatory circuits.
In this review, we discuss current knowledge of RDGN members and their functions, from studies predominantly carried out in Drosophila, beginning with an overview of the protein families that make up the RDGN (see Fig. 1). We then discuss their function in organ and tissue specification, focusing on the recently discovered links both in flies and vertebrates between network members and diverse signaling pathways. We highlight a few examples that illustrate the unifying concepts that have emerged from recent research. Specifically, the high degree of evolutionary conservation of the RDGN members encompasses not only the physical structure of the proteins, but also the functional interactions within the network and with exogenous signaling pathways. Superimposed on this strict conservation, context-specific adaptations reveal the enormous flexibility of genetic circuits, with respect to how they are deployed and how they respond to and integrate with other cellular signals.
|
The proteins belonging to the PAX6, EYA (Eyes absent), SIX and DAC
(Dachshund) families (see Fig.
1) make up the key members of the RDGN. Here, we briefly review
what is currently known about their structure and function (for a more
extensive description of RDGN members, see Pappu and Mardon
(Pappu and Mardon, 2002).
Eyeless/PAX6
Drosophila eyeless (ey) derives its name from the
`eyeless' phenotype that is caused by eye-specific, loss-of-function alleles
of the ey gene (Bridges,
1935). The isolation of null alleles of ey highlighted
its broader functions in the development of the fly embryo and brain
(Table 1)
(Kammermeier et al., 2001
).
The cloning of ey revealed its homology to the vertebrate
Pax6 transcription factors, which encode a subgroup of the large
family of PAX proteins that each contain two DNA-binding motifs: a PAIRED box
and a HOMEOBOX (Fig. 1)
(Quiring et al., 1994
). The
Drosophila genome also contains a second closely linked Pax6
homolog, twin-of-eyeless (toy), which probably arose by gene
duplication during insect evolution
(Czerny et al., 1999
). TOY and
EY are independently required for eye development
(Kronhamn et al., 2002
;
Quiring et al., 1994
).
|
|
EYA family proteins are characterized by a conserved C-terminal domain
called the EYA domain (ED), while the N terminus shows little conservation
aside from the tyrosine rich EYA domain 2 (ED2), which is embedded within a
proline/serine/threonine-rich region (Fig.
1) (Xu et al.,
1997b; Zimmerman et al.,
1997
). These N-terminal domains are crucial for the
transcriptional co-activator function of EYA
(Ohto et al., 1999
;
Silver et al., 2003
). The ED
was initially characterized in flies as a protein-protein interaction domain
that bound the other RDGN members SO
(Pignoni et al., 1997
) and DAC
(Chen et al., 1997
), an
observation that was extended to vertebrate EYA, SIX and DACH families
(Heanue et al., 1999
;
Ohto et al., 1999
).
EYA has been best characterized as a transcriptional co-activator that is
recruited to the DNA of target genes via its interaction with SIX family
members (Ohto et al., 1999;
Silver et al., 2003
).
Recently, a second function has been described for EYA through the
identification of the ED as a catalytic motif belonging to the haloacid
dehalogenase enzyme family (Li et al.,
2003
; Rayapureddi et al.,
2003
; Tootle et al.,
2003
). Recombinant EYA can dephosphorylate tyrosyl phosphorylated
peptides (Rayapureddi et al.,
2003
; Tootle et al.,
2003
) and serine/threonine phosphorylated peptides
(Li et al., 2003
), suggesting
it may be a dual-specificity protein phosphatase. Thus far, only two
substrates, RNA polymerase II (Li et al.,
2003
) and EYA itself (Tootle
et al., 2003
), have been shown to be dephosphorylated by EYA in
vitro, although the in vivo relevance of both findings remains to be
determined. However, the phosphatase function of EYA is required to rescue the
phenotype of the eye-specific eya2 allele
(Rayapureddi et al., 2003
;
Tootle et al., 2003
),
indicating that this property of EYA is utilized in vivo during eye
development in Drosophila.
SO/SIX family members
The SIX family comprises three subgroups, SO/SIX1/SIX2,
SIX4/SIX4/SIX5 and OPTIX/SIX3/SIX6, each with one member
in Drosophila (underlined) and two members in vertebrates
(Kawakami et al., 2000;
Seo et al., 1999
). All family
members are characterized by two conserved domains, the SIX domain, which
mediates protein-protein interactions, and a homeobox DNA-binding domain
(Fig. 1)
(Kawakami et al., 2000
;
Seo et al., 1999
). SIX family
transcription factors are crucial for the development of many tissues and play
an important part in regulating cell proliferation
(Table 1)
(Carl et al., 2002
;
Cheyette et al., 1994
;
Dozier et al., 2001
;
Li et al., 2002
;
Ozaki et al., 2004
). For
example, Six1 is upregulated in a mouse model of metastatic skeletal
muscle cancer, and increased levels of Six1 are associated with a
greater ability to form metastases (Yu et
al., 2004
). The role of SIX1 in malignancy-associated
overproliferation may be to overcome mitotic checkpoints in G2
(Ford et al., 1998
), as it can
directly regulate the transcription of cyclin A1 to induce proliferation
(Coletta et al., 2004
).
The most divergent branch of the SIX family includes Drosophila
OPTIX (Seimiya and Gehring,
2000) and the vertebrate counterparts SIX3 and SIX6, which, unlike
the members of the SIX1/2 and SIX4/5 subfamilies, do not interact with EYA
proteins (Kawakami et al.,
2000
). Instead, work in vertebrates suggests that SIX3/SIX6 act as
transcriptional repressors that are important for proper eye and brain
formation, through their interactions with the GROUCHO (GRO) family of
co-repressors (Box 2)
(Kobayashi et al., 2001
;
Lopez-Rios et al., 2003
;
Zhu et al., 2002
).
Transcriptional repression may not be limited to the SIX3/6 subfamily, as
these proteins interact with GRO co-repressors through an Engrailed homology 1
(eh1) motif that is present in the SIX domain of all SIX proteins
(Kobayashi et al., 2001). In
fact, Drosophila GRO can also interact with SO, and can repress
SO-mediated transcription of a reporter gene, probably by competing with EYA
for binding to SO (Silver et al.,
2003
). Studies in mice have revealed that SIX1 also has a
transcriptional repressor function (Li et
al., 2003
), suggesting that SIX family members might generally
operate as both activators and repressors, depending upon their specific
cofactors and context.
DAC: a novel DNA-binding protein
dachshund (dac) in Drosophila, and its
vertebrate homologs, Dach1 and Dach2, encode novel nuclear
proteins characterized by two conserved domains, the DachBox-N and the
DachBox-C (Fig. 1) (Davis et al., 2001b;
Kozmik et al., 1999
), although
recent studies in Drosophila have suggested that only the DachBox-N
is essential for function (Tavsanli et
al., 2004
). The crystallization of the human DachBox-N has
revealed its structural resemblance to the winged helix/forkhead subgroup of
the helix-turn-helix family of DNA-binding proteins, a finding that had not
been predicted by amino acid sequence homology
(Kim et al., 2002
). Although
no specific DNA-binding sites for DAC have been identified, it has been shown
to bind naked DNA (Ikeda et al.,
2002
). The DachBox-C is thought to be a protein-protein
interaction motif that interacts with the ED of EYA family members
(Chen et al., 1997
). DAC
synergizes with EYA to increase both the size and frequency of ectopic eyes
when the two are expressed together (Chen
et al., 1997
), supporting the model that these two proteins act in
a complex to direct fly eye development. Thus, like SO, DAC (with its
DNA-binding ability) may recruit the transcriptional activator and/or
phosphatase activity of EYA to the promoter of target genes.
Of the RDGN members, DAC remains perhaps the least well mechanistically
understood; the fact that Dach1-null mice die postnatally with no
obvious defects has provided little additional insight into its function
(Table 1) (Backman et al., 2003;
Davis et al., 2001a
). With
respect to transcription, DAC is a novel nuclear factor with the potential to
promote (Ikeda et al., 2002
)
and to repress gene expression (Box
2) (Li et al.,
2002
). A repressor complex between SIX1 and DAC has also been
described that might switch from being a repressor to an activator through the
function of the EYA protein phosphatase
(Li et al., 2003
). All of the
reported experiments that observe a DAC-dependent effect on transcription use
endogenous promoter sequences of several hundred bases or more, raising the
intriguing possibility that the DachBox-N must bind directly to DNA to
co-regulate its target genes. Furthermore, as discussed later in this review
in the context of vertebrate ear development, DAC may, at times, function
independently of, or even antagonistically to, the rest of the RDGN
(Heanue et al., 1999
;
Ozaki et al., 2004
).
Integrating signaling pathways with RDGN components
Studies of the RDGN have revealed new paradigms for transcriptional regulation, and the network has provided a valuable model for studying tissue specification, as discussed later in this review. However, these nuclear factors do not act alone, but are employed coordinately by, and with, components of conserved signaling pathways to achieve the specificity of transcriptional response that is necessary for appropriate development. This section focuses on the regulation of the RDGN genes by different signaling pathways and on examples where the RDGN signals back to these pathways in the context of Drosophila eye development.
DPP and HH signaling regulate RDGN member expression
The Drosophila eye develops in a wave of differentiation that
moves from the posterior to the anterior of the eye disc, which can be
visualized by the progression of the morphogenetic furrow
(Fig. 3A) (for a review, see
Treisman and Heberlein, 1998;
Voas and Rebay, 2004
). The
Decapentaplegic (DPP) and Hedgehog (HH) signaling pathways, which are required
for the establishment and progression of the furrow, influence eye
specification by regulating the expression of the RDGN members.
|
High levels of HH protein are expressed just posterior to the DPP signal in
the morphogenetic furrow, and are required for proper furrow progression
(Fig. 3A)
(Pappu et al., 2003). HH
signaling inside the cell is affected by changes in the transcription factor
Cubitus interruptus (CI); in the absence of signal, CI is cleaved to a shorter
repressor form (CIr), which enters the nucleus and downregulates
target genes, whereas in the presence of HH, the phosphorylation of CI is
blocked, preventing its cleavage and allowing the transcription of target
genes (Chen et al., 1999a
). HH
regulates eya expression by eliminating a transcriptional block,
rather than by directly activating it; removal of CIr is sufficient
to promote eya expression, while the active full-length form of CI
(CIact) is not necessary for eye formation
(Pappu et al., 2003
).
The eye field undergoes a wave of differentiation that is directed by the
expression of DPP and HH at the morphogenetic furrow, together activating or
allowing transcription of the second tier of the RDGN, eya, so and
dac (Curtiss and Mlodzik,
2000; Pappu et al.,
2003
). These three gene products are coincident only at and
surrounding the morphogenetic furrow (Fig.
3B) (Bessa et al.,
2002
; Cheyette et al.,
1994
), where they and the DPP signal come together to direct
terminal differentiation of the eye. Recently, a mechanism has been proposed
that defines the anterior limits of eya and dac expression
(Bessa et al., 2002
).
Homothorax (HTH), a homeodomain protein, and Teashirt (TSH), a zinc-finger
transcription factor, interact with EY anterior to the furrow in Domain II to
form a transcriptional repressor that prevents eya and dac
expression in this region. Expression of hth is itself downregulated
through DPP and EYA, providing a strict boundary of expression between the
undifferentiated and preproneural regions of the eye disc. Further studies of
these diverse transcription factors, alone and in combination, should yield
insights into how this precise program of eye development is orchestrated.
Connections between EGFR signaling and the RDGN
The Epidermal growth factor receptor (EGFR)/RAS/mitogen-activated protein
kinase (MAPK) pathways play conserved roles in growth and differentiation in
many organisms (Widmann et al.,
1999). In the Drosophila eye, EGFR signaling is required
in all cells to prevent apoptosis (Bergmann
et al., 2002
), but is also used selectively to specify many of the
cell types of the eye (for a review, see
Voas and Rebay, 2004
). As
discussed below, the EGFR pathway provides one of the few direct links between
a signaling pathway and the RDGN, where part of the molecular mechanism
linking signaling to the network is understood.
Multiple genetic interactions have suggested that a complex interface
exists between EGFR signaling and the RDGN. For example, mutations in
dac were initially isolated as suppressors of the dominant-active
EGFR allele Ellipse (Elp; Egfr - FlyBase)
(Mardon et al., 1994),
suggesting that DAC plays a positive role in the transduction of the EGFR
signal in the eye. Another RDGN member that is genetically implicated as a
positive transducer of EGFR signaling is EYA
(Rebay et al., 2000
), which is
phosphorylated by MAPK in response to RAS activation
(Hsiao et al., 2001
). Recent
work has demonstrated that MAPK-mediated phosphorylation of EYA increases the
activity of the EYA-SO transcription factor, although it is not absolutely
required for transcription factor function
(Silver et al., 2003
). Thus,
MAPK-mediated phosphorylation of EYA may represent a context specific
mechanism for increasing transcriptional output. Whether MAPK-mediated
phosphorylation regulates other aspects of EYA function, such as its
phosphatase activity, or also phosphorylates DAC and SO, is not known.
The connection between the RDGN and EGFR signaling extends beyond
Drosophila, as molecular data have also linked PAX6 family members to
this pathway in vertebrates. Studies of zebrafish Pax6 have revealed a
conserved MAPK phosphorylation site, serine 413 (Ser413), which is
phosphorylated in vitro and in vivo by MAPK family members
(Mikkola et al., 1999). Ser413
lies within the transactivation domain of Pax6, and, as in Drosophila
EYA, may provide a context-specific mechanism by which zebrafish Pax6 targets
are modulated.
In conclusion, these examples illustrate a conserved link between the RDGN and the EGFR signaling pathway in flies and vertebrates. Whether the underlying mechanisms of this link are identical or distinct remains to be determined. To address this issue it will be informative to explore whether Drosophila EY and vertebrate EYA proteins are regulated by MAPK-mediated phosphorylation, as has been shown for vertebrate PAX6 and Drosophila EYA. If they are, this would indicate extensive conservation of this particular mechanism of signal integration; if regulation appears distinct, this would suggest that the EGFR signaling pathway interfaces with the RDGN using different points of crosstalk in flies and vertebrates.
Antagonistic signaling: determining eye from cuticle
In the formation of the Drosophila eye, two major decisions must
be made by the developing imaginal disc that gives rise to the eye, antenna
and head: one is to distinguish between eye region and antennal region (as
discussed in Box 3); the other
is to distinguish, within the eye region, tissue destined to become eye from
that which destined become head cuticle, using the opposing signals of the
DPP/Transforming growth factor ß (TGFß) and Wingless (WG) pathways.
High levels of DPP at the most posterior region of the eye disc repress the WG
signal and allow the morphogenetic furrow to form, while high levels of WG at
the most dorsal and ventral boundaries of the disc inhibit eye formation (see
Fig. 3A)
(Hazelett et al., 1998). The
RDGN members play important roles in the specification and maintenance of
these expression patterns and may themselves be regulated directly by DPP and
WG signaling.
Genetic manipulations of the WG pathway in the fly have revealed its role
in regulating the genes of the RDGN; for example, loss of WG signaling results
in ectopic morphogenetic furrows and in the ectopic protein expression of EYA
and DAC, while ectopic WG signaling leads to inappropriate cell proliferation
and to the formation of ectopic head cuticle at the expense of eye tissue
(Baonza and Freeman, 2002;
Ma and Moses, 1995
;
Royet and Finkelstein, 1997
;
Treisman and Rubin, 1995
).
Although eye specification is prevented by ectopic WG signaling, the
expression of EY remains unchanged (Baonza
and Freeman, 2002
), suggesting that this block occurs either at
the level of EY protein function, or via downstream components of the network.
Consistent with either of these mechanisms, EYA, SO and DAC protein synthesis
is reduced by ectopic WG pathway activation
(Baonza and Freeman, 2002
). The
downregulation of EYA and DAC is likely to be important for formation of head
cuticle, as in EYA or DAC mutant tissue, head cuticle can form in place of the
eye (I.R., unpublished) (Mardon et al.,
1994
). Could repression of DPP signaling be an indirect mechanism
by which WG downregulates RDGN members? Epistasis experiments indicate that
this is unlikely, as WG-mediated repression cannot be overcome by activation
of DPP/TGFß signaling (Hazelett et
al., 1998
).
However, blocking the transcription of RDGN members is not the only
mechanism that underlies the WG-mediated repression of eye formation, as
ectopic expression of EYA, which leads to elevated levels of SO and DAC
proteins, cannot rescue the loss of eye tissue
(Baonza and Freeman, 2002).
Thus, in tissue with high levels of WG signal, increasing the levels of EYA,
SO and DAC is not sufficient to direct eye formation. This suggests that WG
signaling may have post-translational effects on RDGN function, or may affect
unknown factors that act in parallel to the RDGN. The response of RGDN genes
to multiple signaling pathways makes them key nodes of signal integration, as
seen in the Drosophila eye, for the DPP and WG morphogens.
The RDGN and tissue specification
Although the RDGN has been best characterized for its role in eye
development, insight into its function and into its interactions with
developmentally important signaling pathways has been gained from the
comparative study of different organs and tissues. We discuss three examples
outside the eye in which the RDGN has been particularly well studied. First,
studies of Drosophila gonad development, in which multiple members of
the network play crucial and context-specific roles, have revealed new modes
of regulation and potential combinatorial codes of action of the RDGN members
that may provide insight into the regulation and function of the RDGN in
vertebrate tissues (Bai and Montell,
2002; Bonini et al.,
1998
; Fabrizio et al.,
2003
; Keisman and Baker,
2001
). Second, we describe the role that the RDGN plays in
vertebrate muscle development (Heanue et
al., 1999
), and how studies of this tissue first highlighted the
evolutionary conservation not only of the individual RDGN genes, but also of
the complex meshwork of interactions that links them into a functional
network. Finally, recent analysis of the interplay between PAX, EYA, SIX and
DAC family members in the vertebrate ear placode highlights the additional
regulatory potential that context-specific variations in the use of the RDGN
components provides (Ozaki et al.,
2004
; Zheng et al.,
2003
). Because signal integration and context specificity are
important components of the genetic circuits that are used throughout
development, the principles elucidated from studies of the RDGN are likely to
apply to diverse biological processes.
Sex-specific regulation of RDGN members
Many patterning genes are expressed in homologous regions in the male and
female genital discs of Drosophila. For example, in both sexes,
wg is expressed in a stripe along the anterior-posterior border, and
is flanked by broad stripes of dpp expression
(Keisman and Baker, 2001).
Other genes, including dac
(Keisman and Baker, 2001
;
Sanchez et al., 2001
), are
expressed in a sex-specific manner.
In males, DAC protein expression overlaps the dpp stripes, whereas
in females DAC expression overlaps the central wg expression domain
(Keisman and Baker, 2001;
Sanchez et al., 2001
). DAC
function is important for development of both male and female genitalia, as
males that lack dac have reduced claspers, which are structures of
the external male genitalia, and females that lack dac have defects
in ovarian duct formation (Keisman and
Baker, 2001
).
WG signaling activates DAC protein expression in the female genital discs
(Keisman and Baker, 2001;
Sanchez et al., 2001
).
Strikingly, the opposite effect is observed in male genital discs, where WG
appears to restrict DAC expression
(Keisman and Baker, 2001
;
Sanchez et al., 2001
), as in
the eye (Fig. 4). The converse
is true for DPP signaling, which activates DAC expression in the eye and in
male genital discs, but represses DAC expression in female genital discs
(Fig. 4)
(Keisman and Baker, 2001
;
Sanchez et al., 2001
).
|
EYA is crucial for gonad development in Drosophila
EYA also plays a role in both female and male fertility in
Drosophila (Table 1)
(Boyle et al., 1997;
Fabrizio et al., 2003
). It is
expressed in the somatic gonadal precursor (SGP) cells that associate with the
germ cells and ensure their incorporation into the gonad, and is required for
the maintenance of SGP cell fate (Boyle et
al., 1997
). In this context, EYA may function downstream of WG
signaling, as ectopic activation of the WG pathway induces ectopic EYA and the
recruitment of extra SGPs (Boyle et al.,
1997
). Here, WG plays a positive role in EYA regulation, whereas
in the eye, WG and EYA act antagonistically
(Fig. 4).
By contrast, DPP and EYA have a positive relationship in the developing
gonad, as in the eye; DPP signaling is crucial for EYA expression and for the
formation of SGPs (Boyle et al.,
1997). Thus, context, once again, determines the direction of
interaction between signaling pathways and the RDGN; as in the gonad WG and
DPP together activate EYA in contrast to their opposing functions in the eye
(Fig. 4).
In addition to its roles in patterning the early gonad, EYA also functions
during oogenesis in flies. Three types of somatic follicle cells surround the
developing oocyte and are crucial for proper germ cell development and
function: polar cells, stalk cells and main body epithelial cells
(Spradling, 1993). Ovaries
mutant for eya have extra polar cells, whereas ectopic expression of
eya prevents polar cell specification
(Bai and Montell, 2002
). Unlike
the eye, where Notch and HH signaling exert positive, or at least permissive,
effects on EYA, in the ovary both Notch and HH function antagonistically to
EYA, again illustrating the importance of context on signal integration. For
example, ectopic Notch or HH signaling can reduce EYA protein expression in
the follicle cells and induce the formation of ectopic polar cells
(Bai and Montell, 2002
).
Although the molecular mechanisms underlying Notch- and HH-mediated repression
of EYA have not been elucidated, eya mutant cells exhibit higher
levels of CIact, the transcriptional effector of HH signaling
(Bai and Montell, 2002
),
indicating that a mutually repressive relationship exists between HH signaling
and EYA during the differentiation of ovarian follicle cells.
RDGN members direct muscle specification
In early mouse skeletal muscle development, the expression of
Pax3, a gene related to Pax6 but not orthologous to
ey, overlaps with that of Dach2, and their expression is
mutually regulated through positive feedback loops
(Heanue et al., 1999), similar
to those observed between EY and DAC during Drosophila eye
development (Shen and Mardon,
1997
). Pax3 is required for skeletal myogenesis and, when
overexpressed, can induce Eya2 and Six1 expression
(Ridgeway and Skerjanc, 2001
).
Six1 mutant mice also display defects in myogenesis
(Laclef et al., 2003
), but
Eya2 knockout mice have not yet been reported. Strikingly, when
Eya2 and Six1, as well as Eya2 and Dach2,
are misexpressed in combination, they can synergize to direct the expression
of muscle markers that are indicative of myogenic differentiation, including
PAX3 (Heanue et al., 1999
;
Kardon et al., 2002
). This is
similar to the synergism observed between EYA and SO, and EYA and DAC in
ectopic eye induction in Drosophila
(Chen et al., 1997
;
Pignoni et al., 1997
),
indicating that analogous patterns of interactions between these proteins play
conserved roles in the development of multiple tissues and organ types in
flies and vertebrates.
Signaling by sonic hedgehog (SHH) and WNT family members induce many
muscle-specific factors, and these signals are balanced by negative regulation
through bone morphogenetic proteins (BMPs) and NOTCH
(Parker et al., 2003). For
example Pax3 and Six1 can be induced in a cell culture model
of myogenesis by WNT3A and ß-catenin
(Petropoulos and Skerjanc,
2002
), and Pax3 may also be upregulated by GLI2,
suggesting a positive role for SHH in RDGN regulation
(Petropoulos et al., 2004
).
Furthermore, SIX family members can directly regulate muscle specification
genes, such as myogenin (Spitz et
al., 1998
), making them the possible link between the RDGN, the
signals it interacts with and the muscle-specific genes that control skeletal
muscle development. Further experiments examining the expression and function
of RDGN genes in vivo in response to perturbation of the signaling pathways
that function in mouse skeletal muscle are required to test this hypothesis
and the extent to which the signaling circuitries that operate in flies and
vertebrates are conserved.
Otic development reveals new relationships within the RDGN
Comparisons of RDGN function and regulation in the Drosophila eye
versus vertebrate muscle highlight the striking conservation of relationships
both within the network and with exogenous pathways. Here, we describe how
recent investigations of the RDGN in vertebrate ear development have
illustrated how distinct combinations of regulatory relationships may operate
in different developmental programs (Fig.
5).
|
In contrast to vertebrate skeletal muscle
(Heanue et al., 1999) and the
Drosophila eye (Bessa et al.,
2002
), Dach is not co-expressed with other members of the
RDGN in the otic placode (Ozaki et al.,
2004
), and its expression appears to be independent of either
Pax2 or Eya1 (Heanue et
al., 1999
). Furthermore, expression of Dach1 and
Dach2, which are both normally restricted to the dorsal region of the
otic vesicle, expands ventrally in Six1 mutant mice, suggesting that
Six1 represses Dach
(Ozaki et al., 2004
). Thus, in
the ear, Six1 and Dach provide opposing differentiation
cues, while in the skeletal muscle and fly eye, they work cooperatively in
tissue specification. Further analysis of the molecular function of EYA, DACH
and SIX in these tissues, including the identification of their protein
interactions and target genes, should provide insight into the mechanism that
underlies the sometimes synergistic, sometimes opposing and sometimes
independent, relationships between RDGN members.
Concluding remarks
The RDGN provides a model of signal integration, the study of which may provide us with insights into the broader issue of how signal specificity is brought about in different developmental contexts. Crosstalk between the RDGN members and signaling pathways provides a mechanism for coordinately linking the interdependent processes of differentiation and cell division that are likely to be conserved from flies to humans. Future work aimed at elucidating the conserved roles of these genes and the molecular mechanisms that underlie the context specificity of developmental signaling will benefit greatly from continued comparative investigations of RDGN function in flies and vertebrates.
ACKNOWLEDGMENTS
We apologize to those whose work was not cited owing to space restrictions. We thank T. Tootle and A. Brown for critical reading of the manuscript, and all members of the Rebay Laboratory for helpful discussions. S.J.S. is a Howard Hughes Medical Institute predoctoral fellow and I.R. is supported by the National Institutes of Health.
Footnotes
* Present address: Department of Genetics, Harvard Medical School, 77 Avenue
Louis Pasteur, Boston, MA 02115, USA
REFERENCES
Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M. et al. (1997). A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat. Genet. 15,157 -164.[Medline]
Backman, M., Machon, O., van den Bout, C. J. and Krauss, S. (2003). Targeted disruption of mouse Dach1 results in postnatal lethality. Dev. Dyn. 226,139 -144.[CrossRef][Medline]
Bai, J. and Montell, D. (2002). Eyes Absent, a
key repressor of polar cell fate during Drosophila oogenesis.
Development 129,5377
-5388.
Baonza, A. and Freeman, M. (2002). Control of
Drosophila eye specification by Wingless signalling.
Development 129,5313
-5322.
Bergmann, A., Tugentman, M., Shilo, B. Z. and Steller, H. (2002). Regulation of cell number by MAPK-dependent control of apoptosis. A mechanism for trophic survival signaling. Dev. Cell 2,159 -170.[Medline]
Bessa, J., Gebelein, B., Pichaud, F., Casares, F. and Mann, R.
S. (2002). Combinatorial control of Drosophila eye
development by Eyeless, Homothorax, and Teashirt. Genes
Dev. 16,2415
-2427.
Bonini, N. M., Leiserson, W. M. and Benzer, S. (1993). The eyes absent gene: genetic control of cell survival and differentiation in the developing Drosophila eye. Cell 72,379 -395.[Medline]
Bonini, N. M., Bui, Q. T., Gray-Board, G. L. and Warrick, J.
M. (1997). The Drosophila eyes absent gene directs ectopic
eye formation in a pathway conserved between flies and vertebrates.
Development 124,4819
-4826.
Bonini, N. M., Leiserson, W. M. and Benzer, S. (1998). Multiple roles of the eyes absent gene in Drosophila. Dev. Biol. 196,42 -57.[CrossRef][Medline]
Boyle, M., Bonini, N. and DiNardo, S. (1997).
Expression and function of clift in the development of somatic gonadal
precursors within the Drosophila mesoderm. Development
124,971
-982.
Bridges, C. B. (1935). The mutants and linkage data of chromosome four of Drosophila melanogaster. Z. Biol. 4,401 -420.
Burton, Q., Cole, L. K., Mulheisen, M., Chang, W. and Wu, D. K. (2004). The role of Pax2 in mouse inner ear development. Dev. Biol. 272,161 -175.[CrossRef][Medline]
Callaerts, P., Leng, S., Clements, J., Benassayag, C., Cribbs, D., Kang, Y. Y., Walldorf, U., Fischbach, K. F. and Strauss, R. (2001). Drosophila Pax-6/eyeless is essential for normal adult brain structure and function. J. Neurobiol. 46, 73-88.[CrossRef][Medline]
Carl, M., Loosli, F. and Wittbrodt, J. (2002).
Six3 inactivation reveals its essential role for the formation and patterning
of the vertebrate eye. Development
129,4057
-4063.
Chen, C. H., von Kessler, D. P., Park, W., Wang, B., Ma, Y. and Beachy, P. A. (1999a). Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell 98,305 -316.[Medline]
Chen, R., Amoui, M., Zhang, Z. and Mardon, G. (1997). Dachshund and eyes absent proteins form a complex and function synergistically to induce ectopic eye development in Drosophila. Cell 91,893 -903.[Medline]
Chen, R., Halder, G., Zhang, Z. and Mardon, G.
(1999b). Signaling by the TGF-beta homolog decapentaplegic
functions reiteratively within the network of genes controlling retinal cell
fate determination in Drosophila. Development
126,935
-943.
Cheyette, B. N., Green, P. J., Martin, K., Garren, H., Hartenstein, V. and Zipursky, S. L. (1994). The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12,977 -996.[Medline]
Coletta, R. D., Christensen, K., Reichenberger, K. J., Lamb, J.,
Micomonaco, D., Huang, L., Wolf, D. M., Muller-Tidow, C., Golub, T. R.,
Kawakami, K. et al. (2004). The Six1 homeoprotein stimulates
tumorigenesis by reactivation of cyclin A1. Proc. Natl. Acad. Sci.
USA 101,6478
-6483.
Curtiss, J. and Mlodzik, M. (2000).
Morphogenetic furrow initiation and progression during eye development in
Drosophila: the roles of decapentaplegic, hedgehog and eyes absent.
Development 127,1325
-1336.
Czerny, T., Halder, G., Kloter, U., Souabni, A., Gehring, W. J. and Busslinger, M. (1999). twin of eyeless, a second Pax-6 gene of Drosophila, acts upstream of eyeless in the control of eye development. Mol. Cell 3, 297-307.[Medline]
Davis, R. J., Shen, W., Sandler, Y. I., Amoui, M., Purcell, P.,
Maas, R., Ou, C. N., Vogel, H., Beaudet, A. L. and Mardon, G.
(2001a). Dach1 mutant mice bear no gross abnormalities in eye,
limb, and brain development and exhibit postnatal lethality. Mol.
Cell. Biol. 21,1484
-1490.
Davis, R. J., Shen, W., Sandler, Y. I., Heanue, T. A. and Mardon, G. (2001b). Characterization of mouse Dach2, a homologue of Drosophila dachshund. Mech. Dev. 102,169 -179.[CrossRef][Medline]
Del Bene, F., Tessmar-Raible, K. and Wittbrodt, J. (2004). Direct interaction of geminin and Six3 in eye development. Nature 427,745 -749.[CrossRef][Medline]
Dominguez, M., Ferres-Marco, D., Gutierrez-Avino, F. J., Speicher, S. A. and Beneyto, M. (2004). Growth and specification of the eye are controlled independently by Eyegone and Eyeless in Drosophila melanogaster. Nat. Genet. 36, 31-39.[CrossRef][Medline]
Dozier, C., Kagoshima, H., Niklaus, G., Cassata, G. and Burglin, T. R. (2001). The Caenorhabditis elegans Six/sine oculis class homeobox gene ceh-32 is required for head morphogenesis. Dev. Biol. 236,289 -303.[CrossRef][Medline]
Estrada, B., Casares, F. and Sanchez-Herrero, E. (2003). Development of the genitalia in Drosophila melanogaster. Differentiation 71,299 -310.[CrossRef][Medline]
Fabrizio, J. J., Boyle, M. and DiNardo, S. (2003). A somatic role for eyes absent (eya) and sine oculis (so) in Drosophila spermatocyte development. Dev. Biol. 258,117 -128.[CrossRef][Medline]
Fisher, A. L. and Caudy, M. (1998). Groucho
proteins: transcriptional corepressors for specific subsets of DNA-binding
transcription factors in vertebrates and invertebrates. Genes
Dev. 12,1931
-1940.
Ford, H. L., Kabingu, E. N., Bump, E. A., Mutter, G. L. and
Pardee, A. B. (1998). Abrogation of the G2 cell cycle
checkpoint associated with overexpression of HSIX1: a possible mechanism of
breast carcinogenesis. Proc. Natl. Acad. Sci. USA
95,12608
-12613.
Gallardo, M. E., Lopez-Rios, J., Fernaud-Espinosa, I., Granadino, B., Sanz, R., Ramos, C., Ayuso, C., Seller, M. J., Brunner, H. G., Bovolenta, P. et al. (1999). Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. Genomics 61, 82-91.[CrossRef][Medline]
Halder, G., Callaerts, P., Flister, S., Walldorf, U., Kloter, U.
and Gehring, W. J. (1998). Eyeless initiates the expression
of both sine oculis and eyes absent during Drosophila compound eye
development. Development
125,2181
-2191.
Hanson, I. M., Fletcher, J. M., Jordan, T., Brown, A., Taylor, D., Adams, R. J., Punnett, H. H. and van Heyningen, V. (1994). Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nat. Genet. 6,168 -173.[Medline]
Hazelett, D. J., Bourouis, M., Walldorf, U. and Treisman, J.
E. (1998). decapentaplegic and wingless are regulated by eyes
absent and eyegone and interact to direct the pattern of retinal
differentiation in the eye disc. Development
125,3741
-3751.
Heanue, T. A., Reshef, R., Davis, R. J., Mardon, G., Oliver, G.,
Tomarev, S., Lassar, A. B. and Tabin, C. J. (1999).
Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and
Six1, homologs of genes required for Drosophila eye formation.
Genes Dev. 13,3231
-3243.
Hsiao, F. C., Williams, A., Davies, E. L. and Rebay, I. (2001). Eyes absent mediates cross-talk between retinal determination genes and the receptor tyrosine kinase signaling pathway. Dev. Cell 1,51 -61.[CrossRef][Medline]
Ikeda, K., Watanabe, Y., Ohto, H. and Kawakami, K.
(2002). Molecular interaction and synergistic activation of a
promoter by Six, Eya, and Dach proteins mediated through CREB binding protein.
Mol. Cell. Biol. 22,6759
-6766.
Jang, C. C., Chao, J. L., Jones, N., Yao, L. C., Bessarab, D.
A., Kuo, Y. M., Jun, S., Desplan, C., Beckendorf, S. K. and Sun, Y. H.
(2003). Two Pax genes, eye gone and eyeless, act cooperatively in
promoting Drosophila eye development. Development
130,2939
-2951.
Jun, S., Wallen, R. V., Goriely, A., Kalionis, B. and Desplan,
C. (1998). Lune/eye gone, a Pax-like protein, uses a partial
paired domain and a homeodomain for DNA recognition. Proc. Natl.
Acad. Sci. USA 95,13720
-13725.
Kammermeier, L., Leemans, R., Hirth, F., Flister, S., Wenger, U., Walldorf, U., Gehring, W. J. and Reichert, H. (2001). Differential expression and function of the Drosophila Pax6 genes eyeless and twin of eyeless in embryonic central nervous system development. Mech. Dev. 103,71 -78.[CrossRef][Medline]
Kardon, G., Heanue, T. A. and Tabin, C. J. (2002). Pax3 and Dach2 positive regulation in the developing somite. Dev. Dyn. 224,350 -355.[CrossRef][Medline]
Kawakami, K., Sato, S., Ozaki, H. and Ikeda, K. (2000). Six family genes-structure and function as transcription factors and their roles in development. Bioessays 22,616 -626.[CrossRef][Medline]
Keisman, E. L. and Baker, B. S. (2001). The
Drosophila sex determination hierarchy modulates wingless and decapentaplegic
signaling to deploy dachshund sex-specifically in the genital imaginal disc.
Development 128,1643
-1656.
Kenyon, K. L., Ranade, S. S., Curtiss, J., Mlodzik, M. and Pignoni, F. (2003). Coordinating proliferation and tissue specification to promote regional identity in the Drosophila head. Dev. Cell 5,403 -414.[Medline]
Kim, S. S., Zhang, R., Braunstein, S. E., Joachimiak, A., Cvekl, A. and Hegde, R. S. (2002). Structure of the retinal determination protein dachshund reveals a DNA binding motif. Structure 10,787 -795.[CrossRef][Medline]
Kirby, R. J., Hamilton, G. M., Finnegan, D. J., Johnson, K. J. and Jarman, A. P. (2001). Drosophila homolog of the myotonic dystrophy-associated gene, SIX5, is required for muscle and gonad development. Curr. Biol. 11,1044 -1049.[CrossRef][Medline]
Klesert, T. R., Cho, D. H., Clark, J. I., Maylie, J., Adelman, J., Snider, L., Yuen, E. C., Soriano, P. and Tapscott, S. J. (2000). Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat. Genet. 25,105 -109.[CrossRef][Medline]
Kobayashi, M., Nishikawa, K., Suzuki, T. and Yamamoto, M. (2001). The homeobox protein Six3 interacts with the Groucho corepressor and acts as a transcriptional repressor in eye and forebrain formation. Dev. Biol. 232,315 -326.[CrossRef][Medline]
Kozmik, Z., Pfeffer, P., Kralova, J., Paces, J., Paces, V., Kalousova, A. and Cvekl, A. (1999). Molecular cloning and expression of the human and mouse homologues of the Drosophila dachshund gene. Dev. Genes Evol. 209,537 -545.[CrossRef][Medline]
Kronhamn, J., Frei, E., Daube, M., Jiao, R., Shi, Y., Noll, M. and Rasmuson-Lestander, A. (2002). Headless flies produced by mutations in the paralogous Pax6 genes eyeless and twin of eyeless. Development 129,1015 -1026.[Medline]
Kumar, P. and Moses, K. (2001). EGF receptor and Notch signaling act upstream of Eyeless/Pax6 to control eye specification. Cell 104,687 -697.[Medline]
Laclef, C., Hamard, G., Demignon, J., Souil, E., Houbron, C. and
Maire, P. (2003). Altered myogenesis in Six1-deficient mice.
Development 130,2239
-2252.
Li, X., Perissi, V., Liu, F., Rose, D. W. and Rosenfeld, M.
G. (2002). Tissue-specific regulation of retinal and
pituitary precursor cell proliferation. Science
297,1180
-1183.
Li, X., Oghi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W. et al. (2003). Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426,247 -254.[CrossRef][Medline]
Lopez-Rios, J., Tessmar, K., Loosli, F., Wittbrodt, J. and
Bovolenta, P. (2003). Six3 and Six6 activity is modulated by
members of the groucho family. Development
130,185
-195.
Ma, C. and Moses, K. (1995). Wingless and
patched are negative regulators of the morphogenetic furrow and can affect
tissue polarity in the developing Drosophila compound eye.
Development 121,2279
-2289.
Mardon, G., Solomon, N. M. and Rubin, G. M.
(1994). dachshund encodes a nuclear protein required for normal
eye and leg development in Drosophila. Development
120,3473
-3486.
Mikkola, I., Bruun, J. A., Bjorkoy, G., Holm, T. and Johansen,
T. (1999). Phosphorylation of the transactivation domain of
Pax6 by extracellular signal-regulated kinase and p38 mitogen-activated
protein kinase. J. Biol. Chem.
274,15115
-15126.
Ohto, H., Kamada, S., Tago, K., Tominaga, S.-I., Ozaki, H.,
Sato, S. and Kawakami, K. (1999). Cooperation of Six and Eya
in activation of their target genes through nuclear translocation of Eya.
Mol. Cell. Biol. 19,6815
-6824.
Ozaki, H., Watanabe, Y., Takahashi, K., Kitamura, K., Tanaka,
A., Urase, K., Momoi, T., Sudo, K., Sakagami, J., Asano, M. et al.
(2001). Six4, a putative myogenin gene regulator, is not
essential for mouse embryonal development. Mol. Cell.
Biol. 21,3343
-3350.
Ozaki, H., Nakamura, K., Funahashi, J., Ikeda, K., Yamada, G.,
Tokano, H., Okamura, H. O., Kitamura, K., Muto, S., Kotaki, H. et al.
(2004). Six1 controls patterning of the mouse otic vesicle.
Development 131,551
-562.
Pappu, K. and Mardon, G. (2002). Retinal specification and determination in Drosophila. In Drosophila Eye Development (ed. K. Moses), pp. 5-17. Berlin, Germany: Springer-Verlag.
Pappu, K. S., Chen, R., Middlebrooks, B. W., Woo, C., Heberlein,
U. and Mardon, G. (2003). Mechanism of hedgehog signaling
during Drosophila eye development. Development
130,3053
-3062.
Parker, M. H., Seale, P. and Rudnicki, M. A. (2003). Looking back to the embryo: defining transcriptional networks in adult myogenesis. Nat. Rev. Genet. 4, 497-507.[CrossRef][Medline]
Pasquier, L., Dubourg, C., Blayau, M., Lazaro, L., le Marec, B., David, V. and Odent, S. (2000). A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. Eur. J. Hum. Genet. 8,797 -800.[CrossRef][Medline]
Petropoulos, H. and Skerjanc, I. S. (2002).
Beta-catenin is essential and sufficient for skeletal myogenesis in P19 cells.
J. Biol. Chem. 277,15393
-15399.
Petropoulos, H., Gianakopoulos, P. J., Ridgeway, A. G. and
Skerjanc, I. S. (2004). Disruption of Meox or Gli activity
ablates skeletal myogenesis in P19 cells. J. Biol.
Chem. 279,23874
-23881.
Pignoni, F., Hu, B., Zavitz, K. H., Xiao, J., Garrity, P. A. and Zipursky, S. L. (1997). The eye-specification proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91,881 -891.[Medline]
Punzo, C., Seimiya, M., Flister, S., Gehring, W. J. and Plaza,
S. (2002). Differential interactions of eyeless and twin of
eyeless with the sine oculis enhancer. Development
129,625
-634.
Quiring, R., Walldorf, U., Kloter, U. and Gehring, W. J. (1994). Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 265,785 -789.[Medline]
Rayapureddi, J. P., Kattamuri, C., Steinmetz, B. D., Frankfort, B. J., Ostrin, E. J., Mardon, G. and Hegde, R. S. (2003). Eyes absent represents a class of protein tyrosine phosphatases. Nature 426,295 -298.[CrossRef][Medline]
Rebay, I., Chen, F., Hsiao, F., Kolodziej, P. A., Kuang, B. H.,
Laverty, T., Suh, C., Voas, M., Williams, A. and Rubin, G. M.
(2000). A genetic screen for novel components of the
Ras/Mitogen-activated protein kinase signaling pathway that interact with the
yan gene of Drosophila identifies split ends, a new RNA recognition
motif-containing protein. Genetics
154,695
-712.
Ridgeway, A. G. and Skerjanc, I. S. (2001).
Pax3 is essential for skeletal myogenesis and the expression of six1 and eya2.
J. Biol. Chem. 276,19033
-19039.
Riley, B. B. and Phillips, B. T. (2003). Ringing in the new ear: resolution of cell interactions in otic development. Dev. Biol. 261,289 -312.[CrossRef][Medline]
Rodrigues, A. B. and Moses, K. (2004). Growth and specification: fly Pax6 homologs eyegone and eyeless have distinct functions. Bioessays 26,600 -603.[CrossRef][Medline]
Royet, J. and Finkelstein, R. (1997).
Establishing primordia in the Drosophila eye-antennal imaginal disc: the roles
of decapentaplegic, wingless and hedgehog. Development
124,4793
-4800.
Ruf, R. G., Xu, P. X., Silvius, D., Otto, E. A., Beekmann, F.,
Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr et
al. (2004). SIX1 mutations cause branchio-oto-renal syndrome
by disruption of EYA1-SIX1-DNA complexes. Proc. Natl. Acad. Sci.
USA 101,8090
-8095.
Sanchez, L., Gorfinkiel, N. and Guerrero, I.
(2001). Sex determination genes control the development of the
Drosophila genital disc, modulating the response to Hedgehog, Wingless and
Decapentaplegic signals. Development
128,1033
-1043.
Seimiya, M. and Gehring, W. J. (2000). The
Drosophila homeobox gene optix is capable of inducing ectopic eyes by an
eyeless-independent mechanism. Development
127,1879
-1886.
Seo, H. C., Curtiss, J., Mlodzik, M. and Fjose, A. (1999). Six class homeobox genes in drosophila belong to three distinct families and are involved in head development. Mech. Dev. 83,127 -139.[CrossRef][Medline]
Shen, W. and Mardon, G. (1997). Ectopic eye
development in Drosophila induced by directed dachshund expression.
Development 124,45
-52.
Silver, S. J., Davies, E. L., Doyon, L. and Rebay, I.
(2003). Functional dissection of eyes absent reveals new modes of
regulation within the retinal determination gene network. Mol.
Cell. Biol. 23,5989
-5999.
Spitz, F., Demignon, J., Porteu, A., Kahn, A., Concordet, J. P.,
Daegelen, D. and Maire, P. (1998). Expression of myogenin
during embryogenesis is controlled by Six/sine oculis homeoproteins through a
conserved MEF3 binding site. Proc. Natl. Acad. Sci.
USA 95,14220
-14225.
Spradling, A. C. (1993). Developmental genetics of oogenesis. In The Development of Drosophila melanogaster, Vol. 1 (ed. M. Bate and A. M. Arias), pp. 1-70. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
Tavsanli, B. C., Ostrin, E. J., Burgess, H. K., Middlebrooks, B. W., Pham, T. A. and Mardon, G. (2004). Structure-function analysis of the Drosophila retinal determination protein Dachshund. Dev. Biol. 272,231 -247.[CrossRef][Medline]
Tootle, T. L., Silver, S. J., Davies, E. L., Newman, V., Latek, R. R., Mills, I. A., Selengut, J. D., Parlikar, B. E. and Rebay, I. (2003). The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 426,299 -302.[CrossRef][Medline]
Torres, M., Gomez-Pardo, E. and Gruss, P.
(1996). Pax2 contributes to inner ear patterning and optic nerve
trajectory. Development
122,3381
-3391.
Treisman, J. E. and Heberlein, U. (1998). Eye development in Drosophila: formation of the eye field and control of differentiation. Curr. Top. Dev. Biol. 39,119 -158.[Medline]
Treisman, J. E. and Rubin, G. M. (1995).
wingless inhibits morphogenetic furrow movement in the Drosophila eye disc.
Development 121,3519
-3527.
Voas, M. G. and Rebay, I. (2004). Signal integration during development: insights from the Drosophila eye. Dev. Dyn. 229,162 -175.[CrossRef][Medline]
Wallis, D. E., Roessler, E., Hehr, U., Nanni, L., Wiltshire, T., Richieri-Costa, A., Gillessen-Kaesbach, G., Zackai, E. H., Rommens, J. and Muenke, M. (1999). Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat. Genet. 22,196 -198.[CrossRef][Medline]
Wansink, D. G. and Wieringa, B. (2003). Transgenic mouse models for myotonic dystrophy type 1 (DM1). Cytogenet. Genome Res. 100,230 -242.[CrossRef][Medline]
Wayne, S., Robertson, N. G., DeClau, F., Chen, N., Verhoeven,
K., Prasad, S., Tranebjarg, L., Morton, C. C., Ryan, A. F., van Camp, G. et
al. (2001). Mutations in the transcriptional activator EYA4
cause late-onset deafness at the DFNA10 locus. Hum. Mol.
Genet. 10,195
-200.
Widmann, C., Gibson, S., Jarpe, M. B. and Johnson, G. L.
(1999). Mitogen-activated protein kinase: conservation of a
three-kinase module from yeast to human. Physiol. Rev.
79,143
-180.
Xu, P. X., Cheng, J., Epstein, J. A. and Maas, R. L.
(1997a). Mouse Eya genes are expressed during limb tendon
development and encode a transcriptional activation function. Proc.
Natl. Acad. Sci. USA 94,11974
-11979.
Xu, P. X., Woo, I., Her, H., Beier, D. R. and Maas, R. L.
(1997b). Mouse Eya homologues of the Drosophila eyes absent gene
require Pax6 for expression in lens and nasal placode.
Development 124,219
-231.
Xu, P. X., Adams, J., Peters, H., Brown, M. C., Heaney, S. and Maas, R. (1999). Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat. Genet. 23,113 -117.[CrossRef][Medline]
Xu, P. X., Zheng, W., Laclef, C., Maire, P., Maas, R. L.,
Peters, H. and Xu, X. (2002). Eya1 is required for the
morphogenesis of mammalian thymus, parathyroid and thyroid.
Development 129,3033
-3044.
Xu, P. X., Zheng, W., Huang, L., Maire, P., Laclef, C. and
Silvius, D. (2003). Six1 is required for the early
organogenesis of mammalian kidney. Development
130,3085
-3094.
Yu, Y., Khan, J., Khanna, C., Helman, L., Meltzer, P. S. and Merlino, G. (2004). Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat. Med. 10,175 -181.[CrossRef][Medline]
Zheng, W., Huang, L., Wei, Z. B., Silvius, D., Tang, B. and Xu,
P. X. (2003). The role of Six1 in mammalian auditory system
development. Development
130,3989
-4000.
Zhu, C. C., Dyer, M. A., Uchikawa, M., Kondoh, H., Lagutin, O. V. and Oliver, G. (2002). Six3-mediated auto repression and eye development requires its interaction with members of the Groucho-related family of corepressors. Development 129,2835 -2849.[Medline]
Zimmerman, J. E., Bui, Q. T., Steingrimsson, E., Nagle, D. L., Fu, W., Genin, A., Spinner, N. B., Copeland, N. G., Jenkins, N. A., Bucan, M. et al. (1997). Cloning and characterization of two vertebrate homologs of the Drosophila eyes absent gene. Genome Res. 7,128 -141.[Abstract]