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First published online 23 January 2008
doi: 10.1242/dev.012088
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Research Report |
Department of Neuroanatomy, Max-Planck-Institute for Brain Research, Deutschordenstr. 46, 60528 Frankfurt, Germany.
Author for correspondence (e-mail:
schulte{at}mpih-frankfurt.mpg.de)
Accepted 27 December 2007
SUMMARY
During eye development in D. melanogaster, the TALE-homeodomain protein Homothorax (Hth) is expressed by progenitor cells ahead of the neurogenic wave front, promotes rapid proliferation of these cells and is downregulated before cells exit the cell cycle and differentiate. Here, we present evidence that hth function is partially conserved in vertebrates. Retinal progenitor cells (RPCs) in chicks and mice express two Hth-related proteins, Meis1 and Meis2 (Mrg1), in species-specific temporal sequences. Meis1 marks RPCs throughout the period of neurogenesis in the retina, whereas Meis2 is specific for RPCs prior to the onset of retinal differentiation. Transfection of Meis-inactivating constructs impaired RPC proliferation and led to microphthalmia. RNA-interference-mediated knock-down of expression indicated that progenitor cells expressing Meis1 together with Meis2 proliferate more rapidly than cells expressing Meis1 alone. Transfection of Meis-inactivating constructs reduced the expression of cyclin D1 (Ccnd1) in the eye primordium and co-transfection of cyclin D1 partially rescued RPC proliferation. Collectively, these results suggest that (1) Meis1 and Meis2, similar to hth, maintain retinal progenitor cells in a rapidly proliferating state; (2) they control the expression of some ocular-determination genes and components of the cell cycle machinery; and (3) together with the species-specific differences in Meis1/Meis2 expression, combinatorial expression of Meis family proteins might be a candidate mechanism for the differential regulation of eye growth among vertebrate species.
Key words: Proliferation, Retina, Meis, Cyclin D1, Pax6, Mouse, Chick
INTRODUCTION
Despite the different structure and developmental origin of the vertebrate
lens-eye and the invertebrate compound eye, some components of the regulatory
network that directs eye development are conserved across the animal kingdom.
The transcription factor eyeless/Pax6, for instance, is
essential for eye development in vertebrates and invertebrates, and
atonal and its vertebrate homolog Ath5 (also known as
Atoh7) are important regulators of retinal neurogenesis in both
systems (Kozmik, 2005
;
Vetter and Brown, 2001).
However, examples of non-conservation are also known, which include
dachshund (dac) and its vertebrate homologs Dach1
or Dach2, or apterous and the closely related Lhx2
(Davis et al., 2001;
Davis et al., 2006;
Porter et al., 1997). The
molecular network that controls ocular differentiation is, thus, only
partially conserved.
During development of the vertebrate neural retina, six classes of neurons
and one class of glia are generated from multipotent progenitor cells over a
long developmental period and in overlapping neurogenic waves
(Livesey and Cepko, 2001).
Retinal ganglion cells (RGCs) are always born first (beginning by E10.5 in the
mouse or late E2 in the chick), followed by the other retinal cell classes
(Prada et al., 1991;
Young, 1985). Postmitotic
neurons in the compound eye of Drosophila melanogaster, by contrast,
are generated in the wake of a single neurogenic wave, the morphogenetic
furrow (MF), which sweeps across the eye imaginal disc during the third larval
instar (Heberlein and Treisman,
2000). Proliferating progenitor cells ahead of the MF express the
TALE-homeodomain protein Homothorax (Hth), which together with the Pax6
homolog Eyeless (Ey) and the zinc-finger protein Teashirt (Tsh) promotes
rapid, asynchronous proliferation of retinal progenitor cells and prevents
their premature differentiation (Bessa et
al., 2002). The targets of hth in the eye imaginal disc
and its mechanism of action are not yet known.
Vertebrate homologs of Hth are the Meis family proteins Meis1, Meis2 (Mrg1)
and Meis3 (Mrg2). Meis proteins were first identified as co-factors of other
homeodomain-containing proteins and play multiple roles in development and
disease (Berkes et al., 2004;
Burglin, 1997;
Mercader et al., 1999;
Moens and Selleri, 2006;
Nakamura et al., 1996).
Meis1 and Meis2 are expressed in the eye, but only
Meis1-deficient embryos have been generated to date, and these display defects
in angiogenesis and eye development
(Azcoitia et al., 2005;
Hisa et al., 2004). The
precise function of Meis1 and Meis2 in the retina is still
largely unknown. Here, we provide evidence based on gain-of-function and
knock-down experiments, and on the expression of function-blocking constructs
in chick embryos that both proteins play an evolutionary conserved role in
maintaining the rapidly proliferating state of early retinal progenitor
cells.
MATERIALS AND METHODS
In situ hybridization and immunochemical detection
The following probes were used to analyze gene expression in mice and
chicks: chick Meis1 [nucleotides (NT) 1-711], chick Meis2
(NT 1-818), mouse Meis1 (NT 247-1122), mouse Meis2 (NT
558-1056) and mouse Pax6
(Grindley et al., 1995). All
other probes were gifts of C. Cepko (Harvard Medical School, Boston, MA), C.
Tabin (Harvard Medical School, Boston, MA), F. Pituello (University P.
Sabatier, Toulouse, France) and J.-M. Matter (University of Geneva, Geneva,
Switzerland) or were cloned with gene-specific primers (primer sequences are
available upon request). The dilutions of primary antibodies were: polyclonal
anti-Meis2 1:2000 (A. Buchberg); purified monoclonal anti-Pax6 Fab-fragments
1:5000 (Developmental Studies Hybridoma Bank), polyclonal anti-RCAS (p27)
1:10000 (Charles River Laboratories, CT), polyclonal anti-GFP 1:1000
(Molecular Probes, OR), polyclonal anti-phosphorylated histone H3 (pH3) 1:1000
(Upstate Biotechnology, NY), polyclonal anti-Myc tag 1:300 (Upstate
Biotechnology). In situ hybridization and immunohistochemical analyses were
performed as described previously
(Engelkamp et al., 1999;
Schulte et al., 1999;
Bumsted-O'Brien et al.,
2007).
|
; Swartz et al.,
2001). Unless stated otherwise, 1 µg/µl of the expression
constructs were electroporated into the right optic vesicle as described
(Schulte et al., 1999). In
experiments performed with pMIWIII, 0.7 µg/µl pMIWIII-GFP was
co-electroporated for visualization. RIS(B) is a replication-incompetent
derivative of RCASBP(B), in which the env-gene has been interrupted
by introducing a premature stop codon. Infectious RIS(B) viral particles were
produced in cell culture by supplying the avian (A)-envelope in trans. For
RNA-interference (RNAi)-mediated knock-down of expression, the psiSTRIKE-U6
Hairpin Cloning System was used (Promega, Mannheim, Germany; see Fig. S1 in
the supplementary material) and 0.5-1 µg/µl of the RNAi targeting
constructs was electroporated into the right optic vesicle.
Analysis of cell proliferation and cell death
pMES or pMES-MeisEnR were electroporated into the right optic vesicle at
HH11. Forty-eight hours later, at HH22, BrdU labeling was performed with the
BrdU Labeling and Detection Kit I (Roche, Mannheim, Germany); labeling
duration was 2 hours. Apoptotic cells were determined with the In Situ Cell
Death Detection Kit (Roche). As a control for the labeling procedure, sections
were treated with 200 U/ml DNAse I for 10 minutes at room temperature.
RESULTS AND DISCUSSION
Spatial-temporal expression of Meis family members in mouse and chicken
Meis2 is expressed in the anterior neural plate of
Hamburger-Hamilton stage 7 (HH7) chick embryos
(Fig. 1A). Later,
Meis2 was strongly expressed in the optic vesicle and optic cup,
where it co-localized with Pax6
(Fig. 1B,F-F'').
Strikingly, expression of Meis2 was downregulated in the retina after
late E2 in a central-to-peripheral wave, which paralleled the appearance of
RGC-competent, Ath5-expressing cells
(Fig. 1C,D). By HH25,
Meis2 was absent from RPCs with the exception of the nasal retinal
periphery, which reflects the slight delay in maturation of the nasal compared
with the temporal retina in chicken (Fig.
1E, arrowhead) (Prada et al.,
1991). Meis2 expression in the chick is, therefore,
specific for progenitor cells ahead of the RGC differentiation wave. This
expression pattern is unique amongst known RPC markers (e.g. Pax6,
Six3 and Optx2), which continue to be expressed when postmitotic
neurons and glia are generated. The related protein Meis1 was also expressed
by RPCs, but onset of expression lagged behind that of Meis2 and
expression continued throughout the period of proliferation
(Fig. 1G-J).
Meis2-specific transcripts were also detected in the mouse eye
anlage, but expression was lost prior to optic vesicle invagination
(Fig. 1K,L). Meis1 was
strongly expressed in the mouse optic vesicle and expression continued into
postnatal development (Fig.
1M,N and data not shown). Meis3 was not detected in the
eyes of either species at the embryonic stages analyzed (data not shown). RPCs
in chicks and mice, thus, express different combinations of Meis1 and
Meis2 over time: self-renewing RPCs in the early eye anlage of both
species express Meis1 together with Meis2. Meis2 expression
is terminated before the onset of retinal differentiation, at the late optic
vesicle stage in mice, but just ahead of the RGC production front in
chicken.
Meis1 and 2 are required for rapid progenitor cell proliferation
The presence of Meis1 and Meis2 in proliferating and undifferentiated cells
of the early retina suggests that both proteins promote self-renewal of these
cells. Moreover, rapid asynchronous cell proliferation in the D.
melanogaster eye imaginal disc is restricted to cells expressing the
Meis-related protein Hth, and loss-of-function and gain-of-function studies
have demonstrated that hth is both necessary and sufficient for
progenitor cell proliferation (Bessa et
al., 2002; Dominguez and
Casares, 2005; Heberlein and
Treisman, 2000). We therefore hypothesized that the normal
proliferative capacity of early vertebrate RPCs might, at least in part,
depend on the presence of functional Meis proteins in these cells.
|
; Inbal et al.,
2001). Twenty-four hours following introduction of
MeisEnR and/or GFP into the right optic vesicle (HH15-16),
the right transfected and left control eyes were similar in size
(Fig. 4 and data not shown).
From HH21-22 onwards, however, the transfected eyes were severely
microphthalmic (80%, n=12/15) compared with non-electroporated,
GFP- or Meis2HA-transfected eyes (wild type, n=13
embryos; GFP, n=12; Meis2HA, n=9;
Fig. 2A-B' and data not
shown) and often exhibited an apparent partial transformation of the pigmented
epithelium to retina (Fig. 2C).
MeisEnR-induced microphthalmia was associated with a reduction in the
total number of cells per retina. Upon dissociation of transfected HH25
retinae, we counted an average of 9.06x105
cells/GFP-transfected retina (s.e.m.=0.3001; n=3) compared
with 4.41x105 cells/MeisEnR-transfected retina
(s.e.m.=0.6899; n=3). Retinae transfected with RNAi-targeting
constructs against Meis1 and Meis2 contained an average of
5.15x105 (s.e.m.=0.856; n=3) cells per retina. These
figures correlate well with those determined by others
(Dutting et al., 1983) and
demonstrate that transfection of Meis-inactivating constructs reduced retinal
cell counts. To determine whether this resulted from reduced progenitor cell
proliferation or enhanced cell death, we labeled retinae 24 hours after
transfection, a time before morphological changes of the eye became apparent,
with the thymidine analog BrdU. Two hours after BrdU injection, 61.7%
(±1.07 s.e.m.; n=13 embryos) of the GFP-expressing
cells, but only 27.8% (±2.63 s.e.m.; n=17) of the
MeisEnR/GFP-expressing cells had incorporated the label
(Fig. 2D-F). To control for
possible non-specific effects, several other homeodomain-EnR fusion proteins
were misexpressed in the eye and were found to not affect progenitor cell
proliferation (data not shown). TUNEL labeling indicated that MeisEnR
transfection does not compromise cell survival
(Fig. 2G-I).
|
). Upon retroviral misexpression of MeisEnR, the vast
majority of clones contained only 2-3 cells/section with a second peak of 5
cells/clone/section (n=85 clones;
Fig. 2L). Although retinal
progenitor cells can divide in the presence of MeisEnR, Meis function
nevertheless appears to be required for the rapid proliferation characteristic
of early RPCs (Li et al.,
2000). To determine the relative contribution of Meis1 and Meis2 to RPC proliferation we performed RNAi-mediated knock-down of each gene alone and in combination (Fig. 3A-E and see Fig. S1 in the supplementary material). Following knock-down of Meis1, the mitotic index of RPCs, visualized by detecting the mitosis-specific phosphorylated form of histone H3 (pH3), decreased by 26.8% (±1.4 s.e.m.; n=6 embryos) compared with RPCs transfected with GFP or a randomized targeting sequence. Following Meis2 knock-down, the mitotic index decreased by 30.2% (±1.5 s.e.m.; n=6) compared with the control, whereas simultaneous knock-down of Meis1 and Meis2 or forced expression of Meis2EnR lead to a 59.53% (±0.19 s.e.m.; n=5) and 56.03% (±1.5 s.e.m.; n=3) reduction of the percentage of mitotic cells, respectively. Thus, the mitotic index of RPCs was more profoundly reduced when expression of both Meis genes was knocked-down than in each of the single knock-downs. These results led us to conclude that Meis1 and Meis2 do not function redundantly in the early chick retina, but instead act together to control RPC proliferation. If this were the case, one would expect that RPC proliferation would drop during normal chick development when cells downregulate Meis2 expression (but retain Meis1) after late E2. Indeed, the BrdU index of RPCs was seen to decline between HH18 and HH25 following a central-to-peripheral gradient (see Fig. S2 in the supplementary material).
|
;
Sicinski et al., 1995).
Following MeisEnR expression, cyclin D1 was markedly reduced (in 86%
of the embryos, n=6/7; Fig.
3F,H,I), whereas expression of the related cyclin D2 was normal
(Fig. 3G,J). Transfection of
cyclin D1 together with MeisEnR partially rescued the RPC
proliferation defects we had observed after transfection of MeisEnR
alone (Fig. 3K-N; n=6
embryos for each condition). Meis2 overexpression failed to induce
cyclin D1 expression (data not shown; n=12). Our finding that Meis
function is important for RPC proliferation and cyclin D1 expression, together
with earlier studies that have associated cyclin D1 levels with the modulation
of cell cycle kinetics in the retina, suggest that Meis proteins play a role
in the regulation of retinal progenitor cell number through influencing the
expression of cell cycle components (Green
et al., 2003; Locker et al.,
2006; Skapek et al.,
2001; Wang et al.,
2005; Yamaguchi et al.,
2005). Similar observations have been made independently by Bessa
et al. (Bessa et al.,
2008). MeisEnR-transfected cells also failed to express the proneural genes NeuroM and Ath5 (Fig. 3O-R and data not shown; n=5/5). In addition, few MeisEnR-expressing cells could be detected in the retina past HH24, and those that were present were clumped together at the vitreal surface and did not show features of differentiated neurons (see Fig. S3 in the supplementary material). This was surprising, as retinal differentiation is normal in cyclin D1 mutant mice despite the insufficient cell number in their retinae. We therefore investigated whether the expression of other genes that are essential for eye development also depends on Meis function.
Meis proteins are components of the regulatory network that controls eye development in vertebrates
The paired-type transcription factor Pax6 is crucial for vertebrate eye
development and Meis proteins have been shown to directly regulate expression
of Pax6 in the developing lens and pancreas
(Zhang et al., 2002;
Zhang et al., 2006).
Pax6-specific transcripts were decreased in eyes transfected with
MeisEnR (Fig. 4A-D and
see Fig. S3 in the supplementary material). This suggests that Meis1
and Meis2 contribute to the regulation of retinal Pax6
expression. This view is supported by a series of co-transfection experiments
in which transfection of Meis1 or Meis2 together with
Pax6 stimulated the activity of an 
-enhancer-driven
β-galactosidase reporter construct about 1.6-fold over the previously
reported autostimulation by Pax6 alone, whereas co-transfection of
Pax6 with unrelated homeodomain proteins did not elevate enhancer
activity (see Fig. S3 in the supplementary material)
(Kammandel et al., 1999).
Transfection of MeisEnR effectively repressed expression of
Six3 and Chx10 (Vsx2), but not that of other
ocular-determination genes (Fig.
4E-I). RNAi-mediated knock-down of Meis1 together with
Meis2 also reduced retinal Pax6 transcript levels, albeit to
a lesser degree than did MeisEnR transfection
(Fig. 4J,K). Together, these
results place Meis1/Meis2 upstream of Pax6 in retinal
development and indicate that Meis proteins are part of the genetic cascade
that drives neuroepithelial cells towards ocular differentiation.
Progenitor cell proliferation in the developing retina and cortex is
sensitive to changes in the level of Pax6 expression
(Berger et al., 2007;
Grindley et al., 1995;
Manuel et al., 2007;
Schedl et al., 1996). This
raises the possibility that the observed reduction in cyclin D1 expression by
MeisEnR might be a secondary effect of the concomitant decrease in
Pax6 expression in the eye. We therefore tested whether cyclin D1
expression could be rescued by co-transfection with Pax6. This was,
however, not observed (Fig.
4L,M). Overexpression of Pax6 also failed to elevate
cyclin D1 or cyclin D2 expression in the retina, and cyclin D1 and cyclin D2
expression levels were normal following expression of a Pax6-EnR fusion
protein, which had previously been shown to effectively block Pax6
function in the developing central nervous system
(Fig. 4N-P)
(Yamasaki et al., 2001).
Therefore, Meis1/Meis2 control over cyclin D1 expression appears to
be independent of their ability to regulate Pax6 expression.
Collectively, our data integrate Meis proteins into the genetic network
that regulates eye development in vertebrates, place them upstream of cyclin
D1 and Pax6 in RPCs and suggest that they, similar to their
invertebrate homolog Hth, help to maintain retinal progenitor cells in a
rapidly self-renewing state. Homeodomain transcription factors have been
implicated in the tissue-specific regulation of progenitor cell proliferation
in the nervous system and several of the homeodomain proteins that are
expressed in the vertebrate eye anlage, such as Chx10 and
Optx2, are directly or indirectly required for retinal progenitor
proliferation or enhance eye growth when overexpressed
(Burmeister et al., 1996;
Green et al., 2003;
Zuber et al., 1999). Unlike
these proteins, the duration of Meis expression is highly species-specific and
correlates well with the different eye sizes in birds and mammals. For
instance, chicken, which express Meis2 together with Meis1
over a longer developmental period than mice, contain approximately 50-fold
more RGCs than do mice (Rager and Rager,
1976; Strom and Williams,
1998). Although other genes clearly contribute to eye growth too,
the species-specific regulation of Meis family proteins together with their
influence on retinal progenitor cell proliferation present a likely mechanism
as to how species-specific differences in retinal size could have evolved.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/5/805/DC1
ACKNOWLEDGMENTS
We are grateful to E. Laufer for suggesting the strategy to construct RIS(B) and to A. Buchberg, C. Krull, J.-M. Matter, F. Pituello, M. Kengaku and C. Cepko for reagents. We also thank C. Ziegler for excellent technical assistance, H. Martin for help with the RNAi experiments, G. Pflugfelder for helpful discussions and F. Casares for sharing data prior to publication.
Footnotes
* Present address: Department of Optometry and Vision Science, University of
Auckland, Auckland, New Zealand 
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