1 Department of Molecular and Cellular Biology, Baylor College of Medicine, One
Baylor Plaza, Houston, TX 77030, USA
2 Program in Developmental Biology, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030, USA
3 Department of Ophthalmology, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030, USA
* Author for correspondence (e-mail: kchoi{at}bcm.tmc.edu)
Accepted 11 September 2003
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SUMMARY |
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Key words: Drosophila, Dorsoventral eye patterning, Lobe, Serrate, pannier, Iro-C
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Introduction |
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The development of an imaginal disc into an adult structure requires
generation of anteroposterior (AP) and dorsoventral (DV) lineage restrictions.
In antenna, wing and leg imaginal discs, early-arising AP boundary is the
first lineage restriction event. This is followed by DV boundary generation
midway through the growth phase of the disc, which further subdivides these
discs into dorsal and ventral compartments
(Blair, 1995;
Blair, 2001
;
Diaz-Benjumea and Cohen, 1993
;
Garcia-Bellido and Santamaria,
1972
; Milan and Cohen,
2003
; Morata and Lawrence,
1975
; Tabata et al.,
1995
). By contrast, the eye disc does not show a strict anterior
versus posterior lineage restriction
(Morata and Lawrence, 1978
).
AP pattern in the eye disc is established dynamically as the morphogenetic
furrow (MF), a wave of differentiation, progresses anteriorly, resulting in
the distinction of the AP domains. In fact, anterior and posterior domains
correspond to undifferentiated (anterior to MF) and differentiated regions
(posterior to MF) of eye (Ready et al.,
1976
; Wolff and Ready,
1993
), rather than the compartments of different cell lineages
separated by strict lineage restriction boundary. Therefore, the eye disc
remains at anterior undifferentiated ground state until the early third larval
instar, when MF is initiated to generate the AP pattern
(Heberlein and Moses, 1995
;
Lee and Treisman, 2001
).
However, unlike the AP axis, DV lineage restriction and domain-specific gene
expression of DV patterning genes takes place very early during the eye disc
development (Baker, 1978
;
Cho and Choi, 1998
;
Dominguez and de Celis, 1998
).
Consequently, DV lineage restriction, which is secondary event in other
imaginal discs becomes the first lineage restriction event in eye disc and is
crucial for its growth and differentiation.
Eye disc develops into the adult compound eye, which is a highly precise
hexagonal array of 800 ommatidia (Ready et
al., 1976; Wolff and Ready,
1993
). Two chiral forms of these ommatidial clusters are arranged
in mirror image symmetry along the DV midline called equator to form dorsal
and ventral eye. Although the mirror image symmetry is generated during third
instar of development but the subdivision of eye into dorsal and ventral
lineage territories takes place even earlier
(Baker, 1978
;
Cavodeassi et al., 1999
;
Cho and Choi, 1998
;
Dominguez and de Celis, 1998
;
Maurel-Zaffran and Treisman,
2000
; McNeill et al.,
1997
; Papayannopoulos et al.,
1998
), which is responsible to define the site of differentiation
to initiate and promote the growth of eye field.
It has been shown that pnr
(Maurel-Zaffran and Treisman,
2000) and members of Iro-C homeodomain genes viz.,
araucan (ara), caupolican (caup)
(Cavodeassi et al., 1999
;
Gomez-Skarmeta and Modolell,
1996
) and mirror (mirr)
(Kehl et al., 1998
;
McNeill et al., 1997
) are
expressed in the dorsal region of the prospective eye
(Dominguez and de Celis, 1998
;
McNeill et al., 1997
).
pnr and Iro-C genes have been shown to act as dorsal eye
fate selectors and can also specify the ommatidial DV planar polarity
(Cavodeassi et al., 1999
;
Maurel-Zaffran and Treisman,
2000
). pnr, one of the topmost genes known in dorsal eye
gene hierarchy, regulates the expression of down stream Iro-C genes
by Wingless (Wg) signaling (Heberlein et
al., 1998
; Maurel-Zaffran and
Treisman, 2000
). mirr or caup can repress
fringe (fng) and thereby restrict fng expression to
the ventral eye (Cho and Choi,
1998
; Dominguez and de Celis,
1998
). These genetic interactions define a signaling pathway that
contributes towards the positioning of the equator, which is generated at the
boundary of fng-expressing and non-expressing cells. Equator is the
site for activation of Notch (N) signaling and is crucial for growth and
differentiation of the eye (Cho and Choi,
1998
; Dominguez and de Celis,
1998
; Papayannopoulos et al.,
1998
).
In the ventral eye, fng promotes expression of Ser in the
cells close to the DV boundary. Notch ligands Ser and Delta (Dl) in turn
initiates a Ser-N-Dl positive feedback loop that activates N
signaling (Huppert, 1997;
Irvine, 1999
). Ser
plays dual role in eye development. First, Ser contributes to the DV
boundary formation and secondly Ser is required for ventral eye
growth. Expression of Ser in the ventral eye is controlled by
L, which encodes a novel protein containing a poly-glutamine rich
region. L protein shares a conserved C-terminal domain with novel insect,
mouse and human proteins (Chern and Choi,
2002
). L has also been proposed to be a component of
intracellular pathway that transduces N signaling in the ventral eye probably
by interacting with other ventral specific genes such as Ser
(Chern and Choi, 2002
). In
contrast to the restricted expression of pnr and Iro-C in
the dorsal domain, fng and Ser show dynamic expression
pattern during eye disc development. Both genes are preferentially enriched in
the ventral region of early eye discs but are also expressed dorsally as discs
develop further (Cho and Choi,
1998
; Dominguez and de Celis,
1998
; Papayannopoulos et al.,
1998
). Conversely, L is expressed in the entire eye
despite its specific requirement only in the ventral eye development
(Chern and Choi, 2002
).
DV lineage restriction of eye is associated with onset of expression of
dorsal genes (Cavodeassi et al.,
2000). Therefore, it would be important to determine the temporal
relationship between the expression of dorsal eye selectors and the genes
involved in ventral eye development (hereafter L/Ser). This will
provide new insights into when is the first lineage restriction event of DV
boundary formation initiated during eye disc development. Interestingly, we
found that expression of L and Ser is initiated earlier than
pnr and Iro-C in the eye disc. Removal of
L/Ser gene function during early eye development can
completely eliminate the eye field, whereas later when dorsal selector
pnr gene expression is initiated in the dorsal eye, removal of
L/Ser gene function results in selective loss of ventral eye
fate. We also present that removal of pnr or Iro-C gene
function from the dorsal eye cells can revert the dorsal eye fate to the
ventral, which behaves in a similar fashion to the early eye disc in terms of
its sensitivity to L/Ser activity. We also show that early pnr
expression during embryogenesis has little or no functional contribution to DV
patterning of eye. Therefore, we propose that early eye disc has
ventral-equivalent state, even before the onset of the dorsal selector genes
expression, which results in DV lineage restriction event.
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Materials and methods |
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Generation of loss-of-function clones
Loss-of-function clones were generated using the FLP/FRT system of mitotic
recombination (Xu and Rubin,
1993). To generate loss-of-function clones of L in eye,
eyFLP; FRT42 ubi-GFP females were crossed to FRT42D
Lrev6-3 males. For the generation of heat-shock FLP-mediated
clones of L, hsFLP122; FRT42 ubi-GFP females were crossed
to FRT42D, Lrev6-3 males. Eggs were collected for 2 hours
and a single heat shock was administered for 1 hour at 37°C. All larvae
were transferred to 25°C for recovery and further development.
To generate the loss-of-function clones of pnrvx6, y w;+/+ FRT82 pnrvx6/TM6B, males were crossed to eyFLP; FRT82 ubi-GFP females. Iro-C loss-of-function clones were generated by crossing hsFLP122; FRT80, iroDFM3/TM6Tb males with the eyFLP; FRT80, ubi-GFP females.
As pnr and Iro-C genes play important roles in different
developing fields during development, we wanted to generate the flies that
have only the eyes homozygous for the pnr or Iro-C
mutation and in the same mutant eye disc overexpress another gene of interest.
These flies were generated by using the EGUF (eyeless-GAL4
UAS-FLP) system (Stowers and
Schwarz, 1999). EGUF system has been generated by combining the
GAL4/UAS system (Brand and Perrimon,
1993
) and the FLP recombinase system
(Xu and Rubin, 1993
) via the
UAS-FLP transgene (Duffy et al.,
1998
). The ey-GAL4 drives UAS-FLP recombinase
only in the eye and wild-type cells (heterozygous and +/+ twin spot cells) are
selectively eliminated by GMR>hid later during
differentiation (Stowers and Schwarz,
1999
). As the clones are generated earlier by ey-GAL4 and
the wild-type cells are killed later by GMR>hid, the discs get
time to grow.
Temperature shift regimen
Eggs were collected for the genotype, ey-GAL4;
UAS-SerDN (ey>SerDN) from a synchronous
culture for 2 hours. Each egg collection was divided into several batches.
These independent batches were reared at 18°C except for a single shift to
29°C in a 12 hour time window. This single 12 hour heat shock of each
sample was performed during different periods of development spanning from
t=0 hour AEL (after egg laying) to the late third larval instar.
These cultures after the 12 hour exposure to 29°C were returned to
18°C for the later part of development until the discs were dissected and
stained or till the adult flies emerged (superscript DN indicates dominant
negative).
Another temperature shift regimen was carried out for ey-GAL4; UAS-Ush (ey>Ush) in a similar way except the time windows of exposure to restrictive temperature were different (see Fig. 2A for details).
|
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Results |
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Expression of mirr,an Iro-C member, is not initiated in
early first instar eye disc (Fig.
1D, arrowhead) whereas Ser is expressed in entire disc (data not
shown). In early second instar, mirr is restricted to the dorsal eye
(Fig. 1E,E',F,F'),
whereas Ser is also preferentially expressed in ventral with a weaker
expression in dorsal eye disc (data not shown)
(Cho and Choi, 1998).
mirr expression stays in dorsal region of third instar eye disc (data
not shown) (McNeill et al.,
1997
). mirr is expressed in much broader dorsal domain in
comparison to pnr as it is controlled by secreted Wg, which acts
downstream to pnr (Maurel-Zaffran
and Treisman, 2000
). The expression of ara using antibody
against Ara protein was similar to mirr (data not shown).
Pnr activity is not essential for DV patterning during
embryogeneis
We could not detect pnr in the early first instar eye disc
(Fig. 1A), despite its
expression in embryo (Maurel-Zaffran and
Treisman, 2000). The significance of disappearance of pnr
expression between embryogenesis to late first instar larva is not yet clear.
We performed a functional test to determine whether pnr is active in
the eye primordium in the embryo. We misexpressed U-shaped
(Ush) using ey-GAL4 during embryonic development to block
pnr transcriptional activity. Ush, which is normally not expressed in
eye (Maurel-Zaffran and Treisman,
2000
; Fossett et al.,
2001
), encodes a zinc-finger protein that dimerizes with Pnr and
acts as a negative regulator of pnr transcriptional activity
(Haenlin et al., 1997
). The
aim was to determine if pnr has any role in DV patterning of eye
during embryogenesis. We used temperature-shift approach in three different
conditions as shown in Fig. 2A.
First, we maintained the cultures at 29°C all along the development, which
served as control and resulted in no eye
(Fig. 2B,C) to a small eye
phenotype (Fig. 2D) in almost
80% (51/64) of the adult flies scored, also seen by Fossett et al.
(Fossett et al., 2001
).
Second, the cultures were maintained at 18°C until embryonic development
was over and then shifted to 29°C for the subsequent development to block
the pnr activity after embryonic development is over. It resulted in
elimination of the eye field (Fig.
2E) without affecting the antennal development as seen in the
control experiment. Third, we blocked pnr activity during embryonic
development by maintaining the culture at 29°C and then shifting it back
to 18°C for the subsequent part of development and interestingly we found
very subtle or no effect on eye development
(Fig. 2F,G). We also removed
the pnr function during early first instar of larval development and
then shifted the cultures back to 18°C, which also resulted in a normal
eye (data not shown). The results from these experiments further confirm our
earlier conclusions that eye disc development during embryogenesis to early
first instar of larval development is not sensitive to the loss of
pnr gene function.
Lobe mutations suppress ventral eye development
As L and Ser are expressed in eye disc earlier than
dorsal eye genes, we checked for the role of L and Ser
during various stages of eye development. L mutant shows a selective
loss of ventral eye (Fig. 3A)
(Chern and Choi, 2002). We
generated loss-of-function clones of L in the eye during different
time windows using Lrev6-3 (hereafter
L), a null allele of L
(Chern and Choi, 2002
). These
phenotypes can be broadly divided into two groups. First, ey-FLP was
used (Newsome et al., 2000
) to
generate loss-of-function clones of L exclusively in the eye
(Xu and Rubin, 1993
). These
clones showed asymmetric response in the dorsal and the ventral eye.
Loss-of-function clones of L in the dorsal eye did not affect the
ommatidial development (Fig.
3B, arrow, B') but the ventral eye disc clones inhibited the
ommatidial development (Fig.
3B, arrowhead, B') and corresponding phenotypes were also observed
in adult eye (Fig. 3C). In the
adult eye, presence of ommatidia in the wild-type twin spot cells
(L+/L+) for a ventral
(L/L) clone suggested that
L is required for the ventral eye development
(Fig. 3C, arrow). We checked
the fate of the cells in the loss-of-function clones of L by staining
the eye discs with antibody against Pax6 homolog protein Eyeless (Ey). Ey
marks the undifferentiated cells anterior to the morphogenetic furrow in the
third instar disc (Halder et al.,
1998
). We found that in the ventral clones where the eye fate is
blocked, ectopic Ey induction was seen behind the MF
(Fig. 3D,D' arrowhead).
This suggested that in the absence of L gene function the ventral eye
cells remain undifferentiated. As expected, dorsal eye clones where retinal
differentiation was not blocked, did not show any ectopic Ey induction (data
not shown).
|
Ser is required for early eye field development
Ser is known to be the downstream target of genes which affect
ventral eye development, such as fng
(Irvine, 1999;
Papayannopoulos et al., 1998
)
and L (Chern and Choi,
2002
). SerDN, a dominant-negative allele
encoding a truncated form of Ser, is capable of antagonizing wild-type
Ser functions (Hukriede et al.,
1997
). It consists of extracellular domain but lacks the
transmembrane domain of Ser. SerDN was used to generate
loss-of-function phenotype of Ser
(Chern and Choi, 2002
;
Hukriede et al., 1997
;
Kumar and Moses, 2001
). We
used the temperature-dependent expression of the GAL4 enhancer trap
(Brand and Perrimon, 1993
), to
determine the phenocritical period of SerDN overexpression
(ey>SerDN) in the eye
(Kumar and Moses, 2001
). The
rationale was to check the period when the Ser function is crucial
for DV eye field development. Basically, the phenotypes scored in the eye disc
can be grossly classified into three major categories as summarized in
Fig. 4A. First category showed
complete elimination of eye field to a very small eye. Second category
included the eye discs with preferential elimination of the ventral eye
pattern. The third category comprised the discs where there were two antennal
fields also seen by Kumar and Moses (Kumar
and Moses, 2001
). These discs were also accompanied by the
suppression of eye field. The split of the two antennal fields along with
suppression of eye suggests that Ser also plays a role in patterning
of antennal field.
|
Loss-of-function of dorsal selectors change dorsal eye fate to early
ventral-equivalent state
Lack of sensitivity of dorsal cells to L/Ser led us to check for
the role of dorsal selectors in early DV patterning of eye. We generated
loss-of-function clones of pnr in the eye using
pnrVX6, a null allele generated by a deletion of all but
nine amino acids of the coding region
(Heitzler et al., 1996). As
previously described (Maurel-Zaffran and
Treisman, 2000
), loss-of-function clones of pnr changed
the dorsal eye fate to ventral, which resulted in dorsal eye enlargements or
ectopic eye caused by generation of new boundary of the pnr
expressing- and non-expressing cells (data not shown)
(Maurel-Zaffran and Treisman,
2000
). Loss-of-function clones of pnr in the ventral eye
had no effect as pnr is expressed only in the dorsal eye
(Maurel-Zaffran and Treisman,
2000
).
We have seen that before the onset of dorsal selector gene function, the
entire eye disc is sensitive to L/Ser activity. We wanted to check if
the eye disc ventralized by eliminating the dorsal selector gene function
again becomes sensitive to L/Ser acitivity as seen in early eye disc.
Interestingly, we found that if L levels are increased continuously
above the wild-type levels by using ey-GAL4 (ey>L), it
selectively eliminates the ventral eye pattern
(Fig. 5A,B arrows;
Table 1) (J. J. Chern, PhD
Thesis, Baylor College of Medicine, 2003). This suggests that optimum levels
of L are required for ventral eye growth and development. We used
this property of L as an assay system to check if the eye discs when
mutated for dorsal selector gene function can revert back to ventral, which is
sensitive to levels of L gene function. We used the EGUF system
(Stowers and Schwarz, 1999) to
generate eye disc where all the cells other than those mutant for pnr
were ablated using GMR>hid. The rationale of using this approach
is that GMR>hid kills the cells later during eye
differentiation, therefore these mosaic eye discs could grow. Eye disc mutant
for pnr gene function showed dorsal overgrowths in disc
(Fig. 5C) and in adult eyes
(Fig. 5D,
Table 1). By contrast, when
L was overexpressed continuously in eye using
ey-GAL4 driver (ey>L), pnr mutant discs resulted
in very small eye (Fig. 5E,F, arrow and arrowhead; Table 1).
The small eye phenotype was different from either of the two controls used;
ey>L alone causes ventral-specific eye loss
(Fig. 5A,B), whereas EGUF
clones of pnr results in dorsally enlarged eye
(Fig. 5C,D). Therefore, these
results suggest that small eye phenotype was generated because of suppression
of eye by overexpression of L on both dorsal (which has changed to ventral)
and ventral eye margins. Furthermore, we also analysed the fate of cells left
in the small eyes generated by EGUF clones and overexpression of L by
sectioning the adult eyes. The polarity of most of the ommatidia left in these
eyes was dorsal along with a few ventral or with a polarity defect (data not
shown). We also checked the sensitivity of the pnr mutant discs to
Ser activity. Misexpression of SerDN continuously
during development in the same pnr mutant discs at 25°C
completely abolished the eye fate in nearly 99% of discs
(Fig. 5H,
Table 1), and corresponding
phenotypes were also seen in the unhatched pupae that were dissected out to
check their phenotypes (data not shown). These results suggest that removal of
pnr gene function in the eye disc changes the dorsal eye fate to
ventral, which makes the entire disc sensitive to ey>L or
SerDN as observed in early eye disc.
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Discussion |
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Temporal requirement of genes controlling ventral eye
development
It has been shown that loss-of-function phenotypes of L or
Ser are restricted to the ventral eye
(Chern and Choi, 2002). We
checked the spatial as well as temporal requirement of these genes in the
ventral eye pattern formation. We found that extent of loss of ventral eye
pattern in loss-of-function clones of L/Ser varied along the temporal
scale. During early eye disc development, prior to onset of pnr
expression in dorsal eye, removal of L or Ser function
resulted in complete elimination of the eye field, whereas later when dorsal
eye selector genes starts expressing the eye suppression phenotype becomes
restricted only to the ventral eye (Figs
2,
3,
4,
5). Therefore, DV lineage
border in the eye can also be interpreted as the border between the cells
sensitive and insensitive to the L/Ser gene function.
Initial state of eye is ventral equivalent
The eye antennal disc has the most complex origin in the embryo. The eye
disc is initiated from a small group of 70 precursor cells on each side
contributed by six different head segments of the embryo
(Jurgens and Hartenstein,
1993
). These embryonic precursors do not physically separate from
the surrounding larval primordia and are therefore difficult to discern
morphologically.
Once the cells for the eye-antennal disc are committed, these discs proliferate and undergo differentiation into an adult eye, which requires generation of DV lineage restriction in eye. There are possibly three different ways by which genesis of DV lineage in the eye can be explained. Early first instar larval eye disc may initiate either from only dorsal, only ventral or from both DV lineages. Based on our results from studies of expression patterns (Fig. 1) and analysis of mutant phenotypes (Figs 2, 3, 4, 5), we propose that larval eye primordium initially comprises only the ventral-equivalent state (Fig. 6) rather than well-defined DV or dorsal states alone. We have referred the initial state of eye as ventral equivalent state because, at this stage, dorsal and ventral identity is not yet generated. DV lineage restriction is established later after the onset of pnr expression. The cells of the initial ventral-equivalent state are similar to the ventral eye cells that are generated after DV specification. The similarity is in terms of their requirement of L/Ser for growth and maintenance, and the absence of the dorsal selector expression. How dorsal lineage is initiated in the early eye disc is not yet clear. Once the DV lineage restriction is established, N signaling is initiated at the equator, a border between dorsal and ventral compartments. Activation of N signaling promotes proliferation, which is followed by differentiation of eye disc into adult compound eye.
|
Dorsal selectors and Lobe/Ser affect the eye development at
two different tiers
In contrast to enlargements or ectopic eyes induced by loss-of-function
clones of dorsal selectors (Cavodeassi et
al., 1999; Maurel-Zaffran and
Treisman, 2000
), the loss-of-function clones of L or
Ser always resulted in the elimination of the eye fate.
L/Ser are primarily required for the maintenance and development of
ventral or ventral-equivalent state of the eye, whereas dorsal genes establish
the DV border. This suggests that dorsal genes and L/Ser, although
involved in a common goal of generation of DV lineage in eye, probably affect
eye development at two different tiers.
Fng, another essential component of DV patterning in eye, is expressed
preferentially in the ventral domain of early eye disc and is required for
restriction of N signaling to the DV border
(Cho and Choi, 1998;
Dominguez and de Celis, 1998
;
Papayannopoulos et al., 1998
).
Although fng is known to act upstream of Ser in the wing and
eye discs (Irvine, 1999
),
there is also an apparent difference between the two genes. Unlike
L/Ser, the main function of fng seems to affect DV
ommatidial polarity but not the growth
(Cho and Choi, 1998
;
Dominguez and de Celis, 1998
;
Papayannopoulos et al., 1998
).
This suggests that fng may be selectively required for DV patterning
after dorsal selectors initiate domain specification. This may be the reason
why phenotypes of loss-of-function clones of fng are different from
those of L and Ser in the eye. It has been observed that the
pattern of fng expression is not altered in L mutants, and
vice versa, supporting the independent functions of these two genes in
controlling DV border formation and growth of ventral domain (data not
shown).
Functional conservation of dorsal selector Pnr
The function of Pnr in organizing the DV pattern from an initial
ventral-equivalent state raises an interesting question of whether similar
patterning processes occur in other developing tissues and organs.
Interestingly, Pnr is expressed in a broad dorsal domain in early embryos, but
later refined in a longitudinal dorsal domain extending along the thoracic and
abdominal segments. During this stage, Pnr has an instructive and
selector-like function, determining the identity of the medial dorsal
structures (Calleja et al.,
2000). It has been shown that loss of pnr eliminates the
dorsomedial pattern in the larval cuticle whereas the dorsolateral pattern
extends dorsally without cell loss
(Herranz and Morata, 2001
).
This suggests that DV pattern in the larval cuticle is established with the
onset of Pnr expression in the dorsomedial domain, and ventral may be the
initial fate of epidermal cells.
The compound eye of Drosophila shares some similarities with the
vertebrate eye (Hartenstein and Reh,
2002). Like Drosophila, in higher vertebrates dorsal eye
genes (e.g. Bmp4 and Tbx5) also act as `dorsal selectors'
and restrict the expression of genes involved in ventral eye development (e.g.
Vax and Pax2) to the ventral eye
(Koshiba-Takeuchi et al.,
2000
; Peters and Cepko,
2002
). These DV expression domains correspond to developmental
compartments (Peters, 2002
)
and thereby generate DV lineage restrictions in a way similar to
Drosophila eye. Furthermore, conservation is also seen at the level
of genes and probably their functions. For example, Ser has a
vertebrate homolog Jag1, the loss of function of which shows a strong
eye reduction phenotype (Xue et al.,
1999
). Other dorsal eye genes, such as pnr and
Iro-C, are also highly conserved. Iro-C genes are involved
in neural development in vertebrates
(Gomez-Skarmeta and Modolell,
2002
). There is conservation even in the eye patterning mechanism
because the wave of neurogenesis in the vertebrate eye is analogous to the
morphogenetic furrow in the fly eye (Holt
and Harris, 1993
; Neumann and
Nuesslein-Volhard, 2000
;
Peters, 2002
). Therefore, it
would be interesting to see whether the DV lineage in the vertebrate eye also
develops from a ventral-equivalent initial state. It has been observed that DV
patterning regulates the connectivity of retinal ganglion cells to their
targets in brain (Peters,
2002
). Therefore, the study of DV patterning in vertebrate eye
holds immense potential.
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ACKNOWLEDGMENTS |
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