To determine if Sce is developmentally regulated the spatial distribution of Sce transcript and protein was examined during development. In situ hybridization using a Sce cDNA probe showed a general maternal expression in syncytial blastoderm embryos. This ubiquitous expression is maintained until stage 11. However, by stage 13 of development Sce mRNA was restricted to the neuroectoderm with no expression in the epidermis. Later on, at stage 15 of development, Sce transcripts were detected only in the central nervous system (Gorfinkiel, 2004).

Expression pattern of the Sce protein was also analyzed using an anti-Sce antibody. In Western blots, this antibody recognizes predominantly a unique band, corresponding to the mobility of a 58 kDa polypeptide. In embryos, the same expression pattern of the Sce protein was observed as the one detected by in situ hybridization. However, some differences can be observed. For example, at stage 14 of development, although no transcripts are detected in the epidermis, some Sce protein is still present in the epidermis of anterior segments. This observation suggests that Sce translation or stability might be spatially regulated (Gorfinkiel, 2004).

Ubiquitous expression of Sce in all the imaginal discs was detected by either in situ hybridization or antibody staining. This expression in the imaginal discs is in agreement with the requirement of Sce function during all stages of larval development (Beuchle, 2001; Gorfinkiel, 2004).

PcG proteins are chromosomal proteins, which show binding to discrete euchromatic sites in polytene chromosomes. Many of these binding sites overlap among different PcG proteins. The distribution of Sce protein on salivary gland polytene chromosomes was examined. About 110 euchromatic sites of antibody staining were observed in the polytene chromosomes. Fifty-one of the 110 sites overlap with Pc/Ph/Pcl/Psc binding sites; 25 overlap with Pc/Ph/Pcl sites and 6 of them are common to the subset of unique Asx sites. Among the Sce sites are those of known targets of PcG genes, such as the Ant-C and Bx-C clusters. Thus, the extensive co-localization of Sce and other PcG proteins at many chromosomal sites is in agreement with Sce being a functional partner of other PcG proteins in Drosophila (Gorfinkiel, 2004).

Effects of Mutation or Deletion

In a genetic screen for new PcG mutants, a novel Sce allele was identified, Sce^33M2, which does not complement the Sce¹ allele previously identified by Breen (1986). The embryonic phenotype of Sce^33M2 and Sce¹ mutants were analyzed and compared by staining homozygous embryos with antibodies against the protein products of the homeotic gene Ultrabithorax (Ubx). In both mutants, Ubx is misexpressed, but misexpression is more widespread in Sce¹ homozygotes than in Sce^33M2 homozygotes (McKeon, 1991). In the case of most PcG genes, maternally deposited wild-type products rescue homozygous mutant embryos to a certain extent, and this is also true for Sce (Breen, 1986). To analyze embryos that lack maternally deposited wild-type Sce protein, Sce mutant embryos were generated from Sce germ line clones. Sce¹ homozygous embryos obtained from Sce¹ mutant germ cells show the extreme PcG phenotype reported previously (Breen, 1986). In contrast, Sce^33M2 homozygotes derived from Sce^33M2 mutant germ cells show less severe homeotic transformations and paternally rescued Sce^33M2/+ animals develop into viable adult flies. Taken together, these results suggest that Sce^33M2 is a weaker allele than Sce¹ (Fritsch, 2003).

Sce mutant clones in imaginal discs were analyzed for misexpression of homeotic genes. Clones of Sce¹ or Sce^33M2 mutant cells were induced during the first larval instar and analyzed 96 h after clone induction. In these experiments, Sce mutant cells were identified by the absence of a GFP-expressing marker gene. Both Sce¹ and Sce^33M2 mutant clones show misexpression of Ubx and Abdominal-B (Abd-B) protein, although misexpression is slightly weaker in Sce^33M2 mutant clones compared to Sce¹ mutant clones. These results show that silencing of homeotic genes requires Sce function throughout development. The clonal analysis also supports the allele classification; Sce^33M2 appears to be a weaker allele than Sce¹(Fritsch, 2003).

By recombination mapping, Breen (1986) located Sce¹ to region 3-92 on the genetic map. This map position approximately corresponds to the chromosomal interval harboring the Ring locus in 98A. A candidate gene approach was used to test whether Sce encodes Ring, and the Ring coding sequence was examined for molecular lesions. The Ring coding region was PCR-amplified from genomic DNA prepared from Sce¹ and Sce^33M2 mutants and sequenced. This analysis revealed that both alleles show a distinct molecular lesion. Sce¹ carries a 410 bp deletion that removes the codons for the C-terminal 113 amino acids as well as the intron and 12 nucleotides of the 3′ untranslated region downstream of the termination codon. The Ring ORF in the Sce¹ allele therefore encodes a truncated Ring protein (Ring_1-322) that is fused in frame to 23 novel amino acid codons that are encoded by the 3' UTR. The predicted polyadenylation signal is still present in the Sce¹ allele. In Sce^33M2, a single base substitution was found that changes the codon for Arg⁶⁵ in the middle of the RING finger into a codon for Cys. This arginine, immediately adjacent to the histidine in the C3HC4 Ring-finger, is conserved in the mammalian RING1A and RING1B proteins and in database searches no Ring finger protein was found containing a cysteine at this position. Substitution of Arg by Cys at this position might perturb the structure of the RING finger and/or interaction with other proteins. The slightly weaker phenotype of Sce^33M2 mutants compared to Sce¹ mutants suggests that this protein is probably expressed and provides at least some Sce⁺ function. Taken together, the molecular characterization of these two Sce alleles reveals that Sce encodes the Ring protein. This locus is therefore called Sce/Ring (Fritsch, 2003).

Reconstitution of stable Drosophila PRC1 in vitro has been shown to require the Ring protein (Francis, 2001). This study shows that Sce encodes Ring and, together with earlier studies, that mutations in Sce/Ring cause misexpression of homeotic genes that is as severe as misexpression caused by mutations in Psc, ph and Pc, the other three PRC1 core components. The extreme PcG phenotype of Sce mutants provides strong support for the idea that Sce/Ring protein is strictly required for formation and function of PRC1 in Drosophila. At present, it is not known how Sce/Ring integrates into PRC1 in Drosophila but studies on the mammalian RING1 proteins suggest that the C-terminal domain of RING1B interacts with the C-terminal repressor domain of M33, the mammalian homologue of Drosophila Pc (Schoorlemmer, 1997). Similarly, in yeast two-hybrid assays, the RING finger of RING1B has been found to interact with the RING finger of Bmi-1, the orthologue of Psc in the mammalian PRC1 complex (Hemenway, 1998: Satijn, 1999; Levine, 2002). Hence, it appears that RING1 proteins contain two functional domains, an N-terminal RING finger domain that interacts with RING finger proteins such as Bmi-1 and a C-terminal domain that interacts with M33/Pc. The molecular lesions in Sce¹ and Sce^33M2 and the strong PcG phenotypes observed in both mutants suggest that both domains are needed for PcG silencing, although, at present, it is not known whether the mutant proteins encoded by either of these two alleles are expressed as stable polypeptides in vivo. Formally, the possibility that Sce¹ is not a null allele cannot be excluded, although the extreme PcG phenotype suggests that it may be a null mutation with respect to homoetic gene silencing (Fritsch, 2003).

The strong PcG phenotype of Sce/Ring mutants in Drosophila provides an interesting comparison with the phenotypes of Ring1 A and Ring1 B mutant mice. Ring1 A null mutant mice show anteriorly directed transformations, whereas most other mouse PcG mutants show posteriorly directed homeotic transformations and misexpression of HOX genes (del Mar Lorente, 2000). Thus, it is not clear whether Ring1 A is needed for HOX gene silencing. Mice that are homozygous for a null mutation in Ring1 B die during gastrulation, making it difficult to assess the requirement for Ring1B in HOX gene silencing (Voncken, 2003). However, recent studies show that mice carrying a hypomorphic Ring1 B mutation show very weak PcG phenotypes and subtle misexpression of HOX genes (Suzuki, 2002). This suggests that at least RING1B is indeed required for HOX gene silencing in vertebrates. In summary, the results of this study show that Sce encodes Ring and that, in Drosophila, the Sce/Ring protein is critically required for PcG silencing during embryonic and larval development (Fritsch, 2003).

Sce¹/Sce¹ embryos from Sce¹/+ mothers (m⁺, z⁻ embryos) die as first instar larvae and show very weak posteriorly directed segmental transformation. In such larvae the ventral denticle belts of A7 develop with some A8 character (Breen, 1986). Sce¹/Sce¹ embryos derived from Sce¹/Sce¹ germ-line mutant females crossed to Sce¹ males (m⁻, z⁻ embryos) show extreme posteriorly directed segmental transformation. All the thoracic and abdominal segments are transformed to A8 and head involution is blocked (Breen, 1986). Moreover, these mutants showed an anterior de-repression of the homeotic gene products such as AbdB (Fritsch, 2003). To test whether Sce¹ allele is a lack of function mutation, a deficiency that uncovered Sce locus was sought. All available deficiencies were examined at 98A, a region where Drosophila Ring was located. Df(3R)IR16, whose breakpoints include 97F1-2; 98A on the cytological map, is lethal over Sce¹. In addition, homozygous Sce¹/Sce¹ germ-line mutant females crossed to Sce¹ males produce embryos that have identical phenotypes than when crossed to Df(3R)IR16 males. This result indicates that Df(3R)IR16 is a genuine deficiency for the Sce locus and suggest that Sce¹ is a null allele (Gorfinkiel, 2004).

To verify that Drosophila Ring is Sce, the phenotype of Sce¹ (m⁻, z⁻) embryos was examined when Drosophila Ring/Sce was over-expressed using arm-GAL4 driver. A complete rescue of the embryonic phenotype was observed in such embryos, which are undistinguishable from wild type embryos. In the resulting embryonic population of the same experiment, there were also zygotic rescued embryos (m⁻, z⁺) that have almost wild type phenotype. To unequivocally distinguish the Sce¹ embryos rescued by ectopic Drosophila Ring/Sce from the rest of the embryonic derived population, UAS-Drosophila Ring/Sce (UAS-Sce) was ectopically expressed using the paired-Gal4 line, which induces ectopic expression in alternate segments. The areas of rescued cuticle in the Sce¹ (m⁻, z⁻ embryos); prd-Gal4/UAS-Sce embryos corresponded to those of prd expression domains. This rescue was visualized by the normalized T1 and T3 denticle belts and was also observed in anterior A2 and posterior A3 denticle belts. It was then asked whether the murine Ring1/Ring1A protein would substitute for the fly Sce protein. As before, Ring/Ring1A was expressed in Sce¹ (m⁻, z⁻) embryos using the lines arm-Gal4 and prd-GAL4 as drivers, and a rescue of the Sce phenotype was observed similar to that seen with Drosophila Ring/Sce. These results further demonstrate that Sce locus encodes for the Drosophila ortholog of vertebrate Ring1/Rnf2 genes and that the function of the Ring proteins is conserved in mice and flies (Gorfinkiel, 2004).

Polycomb group genes are required for neural stem cell survival in postembryonic neurogenesis of Drosophila

Genes of the Polycomb group (PcG) are part of a cellular memory system that maintains appropriate inactive states of Hox gene expression in Drosophila. This study investigates the role of PcG genes in postembryonic development of the Drosophila CNS. Mosaic-based MARCM techniques were used to analyze the role of these genes in the persistent larval neuroblasts and progeny of the central brain and thoracic ganglia. Proliferation in postembryonic neuroblast clones is dramatically reduced in the absence of Polycomb, Sex combs extra, Sex combs on midleg, Enhancer of zeste or Suppressor of zeste 12. The proliferation defects in these PcG mutants are due to the loss of neuroblasts by apoptosis in the mutant clones. Mutation of PcG genes in postembryonic lineages results in the ectopic expression of posterior Hox genes, and experimentally induced misexpression of posterior Hox genes, which in the wild type causes neuroblast death, mimics the PcG loss-of-function phenotype. Significantly, full restoration of wild-type-like properties in the PcG mutant lineages is achieved by blocking apoptosis in the neuroblast clones. These findings indicate that loss of PcG genes leads to aberrant derepression of posterior Hox gene expression in postembryonic neuroblasts, which causes neuroblast death and termination of proliferation in the mutant clones. These findings demonstrate that PcG genes are essential for normal neuroblast survival in the postembryonic CNS of Drosophila. Moreover, together with data on mammalian PcG genes, they imply that repression of aberrant reactivation of Hox genes may be a general and evolutionarily conserved role for PcG genes in CNS development (Bello, 2007).

Genetic analysis indicates that the PcG genes Sce, Scm, Pc, E(z) and Su(z)12 are required for postembryonic neurogenesis in the central brain and thoracic ganglia of Drosophila. In the absence of any one of these genes, several mutant phenotypes are observed in the third-instar CNS: (1) neural proliferation is dramatically reduced and only small numbers of cells are found in neuroblast clones; (2) proliferating postembryonic neuroblasts are absent in most of the mutant clones due to apoptosis; (3) posterior Hox genes are ectopically expressed in the postembryonic neuroblast lineages. It is hypothesized that these phenotypes are causally related, in that loss of PcG genes leads to ectopic Hox gene expression in postembryonic neuroblasts resulting in their premature cell death and, thereby, in drastically reduced neuroblast lineage size. Strong support for this hypothesis is provided by the fact that the mutant lineages proliferate normally if apoptosis is blocked. Corollary support for this notion is provided by the fact that Psc-Su(z)2 mutant clones, which do not show ectopic Hox gene expression, are consistently wild-type-like in size and presence of neuroblast (Bello, 2007).

Numerous genes are required for the continued mitotic activity of neuroblasts during postembryonic life. These findings provide the first demonstration that PcG genes are essential for neuroblast survival and proliferation in the postembryonic CNS. Previous work on PcG gene action during embryonic neurogenesis has demonstrated that the derepression of posterior Hox genes in PcG mutants leads to a change in the segmental determination of neuroblasts and their lineage, but not to their mitotic arrest and death. Thus, the effects of PcG gene loss on neurogenesis are context-dependent and differ during embryonic development as compared with postembryonic development. This is underscored in recent work which indicates that the PcG gene ph is essential for maintaining neuronal identity and diversity during metamorphosis (Bello, 2007).

In postembryonic development of the Drosophila CNS, a remarkable link exists between neuroblast survival and Hox gene expression. In the ventral ganglia, a neuroblast-specific pulse of abd-A during the third instar provides the cue for cell death, which limits the number of progeny produced per neuroblast. These data indicate that this mechanism, which in the wild type relates Hox gene expression to the clone size of neural stem cells, also operates in PcG mutants and is responsible for the PcG mutant phenotypes. Indeed, a general function of PcG genes in postembryonic neurogenesis may be to prevent the premature and widespread operation of this mechanism for temporal regulation of neurogenesis through termination of neuroblast life. It is noteworthy that the Hox gene-dependent activation of apoptosis within the CNS is selective for the neuroblast and does not occur when Hox genes are derepressed in neurons, either during normal development or in misexpression experiments. This explains why the neurons in PcG mutant clones, which were generated before the induction of neuroblast cell death, continue to survive despite the presence of ectopic Hox gene derepression (Bello, 2007).

These data indicate that loss of specific PcG genes in larval neuroblasts leads to ectopic Hox gene expression that is sufficient to cause neuroblast cell death. However, the PcG proteins may also contribute to neuroblast survival by repressing other unidentified target genes which, when derepressed, might result in premature death of postembryonic neuroblasts. Indeed, although deregulation of Hox gene expression is one of the hallmarks of PcG phenotypes in Drosophila, a diverse set of other target genes, including genes involved in cell cycle regulation, are controlled by PcG genes (Bello, 2007).

Interesting parallels to these findings on the role of PcG genes in neural proliferation come from studies of mammalian PcG genes, specifically of the Bmi1 gene. Bmi1 mutant mice develop ataxia, seizures and tremors in early postnatal life, and display a significant reduction in overall brain size, which is particularly severe in the granular and molecular layers of the cerebellum. Strikingly, Bmi1-deficent mice become depleted of cerebellar neural stem cells postnataly, indicating an in vivo requirement for Bmi1 in neural stem cell renewal. Bmi1 deficiency leads to increased expression of the cell cycle regulators p16Ink-4a and p19Arf (both now known as Cdkn2a - Mouse Genome Informatics), and the neurogenesis defect in the mutant mice can be partially rescued by further deleting p16Ink4a. This suggests that one way in which Bmi1 promotes the maintenance of adult stem cells is by repressing the p16Ink4a pathway. However, it is also likely that Hox gene repression through Bmi1 is involved in this process, given that loss of Bmi1 has been shown to cause a deregulation of posterior Hox gene expression in neural stem cells in vitro. Moreover, a direct molecular link between Bmi1 and Hox gene regulation has recently been discovered in mammalian development, in that the promyelocytic leukemia zinc finger (Plzf; Zbtb16 -- Mouse Genome Informatics) protein directly binds Bmi1 and recruits PcG proteins in the HoxD cluster (Bello, 2007 and references therein).

In Drosophila, the homologs of the mammalian Bmi1 gene are the PcG genes Psc and Su(z)2. Psc and Su(z)2 encode very similar proteins and are partially redundant in function, but both genes are eliminated in a deletion in the Psc-Su(z)2 line. Rather surprisingly, mutational loss of Psc-Su(z)2 does not lead to ectopic Hox gene derepression and, in consequence, does not appear to affect neuronal proliferation in the postembryonic CNS of Drosophila. This is in stark contrast to the other five PcG genes investigated, which do play important roles in proliferation control by preventing ectopic Hox gene expression and cell death in postembryonic neuroblasts. The discrepancy between murine Bmi1 and Drosophila Psc-Su(z)2 function in neuronal proliferation suggests that although a general role of PcG genes in neuronal proliferation control may be conserved between mammals and flies, conservation of gene action may not always be retained at the level of individual PcG homologs (Bello, 2007).

In terms of overall development, it is clear that one and the same PcG gene can have very different functions depending on the developmental context in which it acts. For example, as mentioned above, during embryonic neurogenesis the Drosophila Pc gene acts in tagmata-specific differentiation of neuroblasts, in contrast to its role in postembryonic neurogenesis. Moreover, in postembryonic development of imaginal discs, deletions in the Drosophila Psc-Su(z)2 genes have been shown to result in cellular hyperproliferation, which contrasts with the lack-of-proliferation phenotype of Psc-Su(z)2 mutants in postembryonic development of the CNS. Similarly, in the mouse, the Bmi1 gene has been implicated in tumor progression in mantle cell lymphoma, colorectal cancer, liver carcinomas and non-small cell lung cancer, in addition to its role in nervous system development. Nevertheless, in all of the Drosophila and mammalian phenotypes mentioned, deregulation of Hox gene expression appears to be one of the conserved and thus unifying features of PcG gene functional loss (Bello, 2007).

Reference names in red indicate recommended papers.

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date revised: 10 April 2008

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