InteractiveFly: GeneBrief

Six4: Biological Overview | References


Gene name - Six4

Synonyms -

Cytological map position - 77E6-77E6

Function - homeodomain transcription factor

Keywords - ventral mesoderm, gonad formation

Symbol - Six4

FlyBase ID: FBgn0027364

Genetic map position - 3L:20,781,986..20,785,868 [-]

Classification - Homeodomain

Cellular location - nuclear



NCBI links: Precomputed BLAST | EntrezGene
BIOLOGICAL OVERVIEW

Patterning of the Drosophila embryonic mesoderm requires the regulation of cell type-specific factors in response to dorsoventral and anteroposterior axis information. For the dorsoventral axis, the homeodomain gene, tinman, is a key patterning mediator for dorsal mesodermal fates like the heart. However, equivalent mediators for more ventral fates are unknown. This study shows that Six4, which encodes a Six family transcription factor, is required for the appropriate development of most cell types deriving from the non-dorsal mesoderm: the fat body, somatic cells of the gonad, and a specific subset of somatic muscles. Misexpression analysis suggests that Six4 and its likely cofactor, Eyes absent, are sufficient to impose these fates on other mesodermal cells. At stage 10, the mesodermal expression patterns of Six4 and tin are complementary, being restricted to the dorsal and non-dorsal regions respectively. These data suggest that Six4 is a key mesodermal patterning mediator at this stage that regulates a variety of cell-type-specific factors and hence plays an equivalent role to tin. At stage 9, however, Six4 and tin are both expressed pan-mesodermally. At this stage, tin function is required for full Six4 expression. This may explain the known requirement for tin in some non-dorsal cell types (Clark, 2006).

A fundamental question in developmental biology concerns the means by which uncommitted cells become specified to form a diversity of tissues according to their spatial location. In general, it is clear that a relatively small number of signaling and transcription factors are expressed in response to positional information, and in turn, these act combinatorially to regulate the expression of more specialized cell type regulatory factors. There is much interest in understanding the combinatorial regulation of cell type factors, particularly through computational analysis of their cis-regulatory regions. This is hampered, however, by an incomplete understanding of the identity and function of the upstream regulatory mediators themselves (Clark, 2006).

The specification of the mesoderm in Drosophila provides a tractable model system in which to study how the expression of cell type regulators is patterned within a large group of cells that are initially identical. A diverse range of organs derives from the Drosophila mesoderm, including the heart, the somatic and visceral muscles, the fat body and the somatic component of the gonad. For parasegments 4-12, an approximate fate map can be constructed outlining the mesodermal regions that give rise to these organs. Transplantation experiments show that fate determination is dependent on cell position, and therefore, patterning the mesoderm requires positional information. This is provided in part by inductive signaling from the overlying ectoderm, which results in the establishment of specific expression patterns for mesodermal transcription factors (Clark, 2006).

Along the anteroposterior axis, the parasegmental mesoderm is divided into two domains that correspond to the action of the pair rule genes, even skipped (eve) and sloppy paired (slp). The eve domain includes the cells underlying ectodermal stripes of hedgehog (hh) and engrailed (en) expression, and these genes participate in the development of the tissues that derive from this region. The action of hh is antagonized by that of wingless (wg), which signals to cells of the slp domain leading to body wall muscle and heart development. In the slp domain, twist (twi) is expressed at a high level and contributes to the development of the somatic muscles, while Notch signaling modulates twi to low levels in the eve domain (Clark, 2006 and references therein).

In the dorsoventral axis, the homeodomain transcription factor, Tinman (Tin), plays a central role in establishing dorsal mesoderm fates. In the dorsal region, ectodermal Decapentaplegic (Dpp) signaling maintains the expression of tin, which is lost from the remainder of the mesoderm following gastrulation. Tin and Dpp combine with factors involved in anteroposterior patterning to establish the primordia of the various dorsal mesodermal organs. For example, in the dorsal slp domain, Tin cooperates with Wg to activate specific sets of target genes, leading to heart and dorsal muscle development. Conversely, the visceral mesoderm is formed in the dorsal eve domain through the activation of bagpipe by Tin and Dpp and its repression by wg/slp. Apart from its dorsal function, tin also has a poorly understood role in the development of more ventral mesodermal fates (Clark, 2006 and references therein).

Outside the dorsal domain, it has been suggested that the non-dorsal mesoderm is divided into ventral and dorsolateral domains. This was based on the response of fat body cells to Wg signaling, although it is not clear whether this distinction has a genetic basis. The dorsolateral domain contains cells with dual fat body/somatic gonadal precursors (SGP) competence, although normally only those cells in parasegments 10-12 take on an SGP fate. Apart from the role of Tin dorsally, the patterning of mesodermal fates in the dorsoventral axis is poorly understood. Nevertheless, recently it has been demonstrated that Pox meso exhibits an early function, partially redundant with the function of lethal of scute, in demarcating the 'Poxm competence domain', a domain of competence for ventral and lateral muscle development and for the determination of at least some adult muscle precursor cells (Duan, 2007). A major unanswered question is whether there are factors in the non-dorsal mesoderm that perform functions complementary to those of Tin in the dorsal region. A candidate for such a factor is the Six family homeodomain protein, Six4. In mouse, Six1, Six4, and Six5 genes are coexpressed during myogenesis, while Six1 and Six4 at least are required during mesoderm development (Grifone, 2005). In human, reduction of SIX5 expression may underlie some of the abnormalities associated with Type 1 Myotonic Dystrophy (DM1) (Fillipova, 2001: Klesert, 1997; Thornton, 1997). In Drosophila, the sole Six4/Six5 homologue, Six4, is the only Six homeoprotein expressed in the early mesoderm, and its mutation (Seo, 1999; Kirby, 2001) disrupts gonad and muscle development (Clark, 2006).

Evidence that Six4 is a key mesodermal patterning factor and is necessary for the correct development of various cell types deriving from the non-dorsal mesoderm, including fat body, SGP, and somatic muscles. Correspondingly, at stages 10/11, Six4 is expressed in non-dorsal mesoderm in a complementary pattern to tin. Moreover, with its cofactor Eyes absent (Eya), Six4 is sufficient to drive the specification of certain non-dorsal fates. In addition, these results clarify the function of tin in ventral mesodermal cells: it is proposed that earlier in development (at stages 8/9), part of tin's function ventrally is to initiate expression of Six4 (Clark, 2006).

Using a GFP reporter gene construct (referred to as Six4-III-GFP), an enhancer was identified within the Six4 third intron that activates GFP in a pattern corresponding closely to the mesodermal expression of Six4 RNA. At stage 9, Six4-III-GFP is coexpressed with D-Mef2 in a broad mesodermal domain. Subsequently, by stage 10, GFP expression becomes largely restricted ventrally, although some perduring protein remains in the dorsal region. At this point, lateral/ventral Six4-III-GFP expression is complementary to the dorsal expression of Tin (although the two are coexpressed earlier). Once restricted, the dorsal limit of Six4-III-GFP expression coincides with that of serpent (srp) protein, which marks the dorsolateral fat body cells. The levels of Six4 mRNA and Six4-III-GFP expression are modulated in the anteroposterior axis of the segment, being stronger in the slp domain (between the dorsolateral Srp clusters of the eve domain). This anteroposterior modulation of Six4 expression resembles that of twi, raising the possibility that different levels of protein have different functional consequences (Clark, 2006).

At stage 10, inductive dpp signaling from the dorsal ectoderm acts to maintain tin expression, thereby driving the dorsal restriction of Tin. Conversely, the ventral restriction of Six4 may depend on an inhibitory effect of dpp signaling. Consistent with this, misexpression of dpp throughout the mesoderm reduces expression of Six4 RNA to a low level. Thus, it is suggested that dpp signaling acts to establish two, non-overlapping spatial domains of gene expression in the mesoderm: a dorsal domain expressing tin and a ventral and lateral domain in which Six4 is expressed. Six4 is therefore a candidate for the counterpart of tin in patterning more ventral mesodermal fates (Clark, 2006).

Six4 is a key factor for the development of a variety of tissues that originate from the non dorsal mesoderm. It is required for the SGPs, fat body precursors and specific lateral and ventral muscles and is likely to be a competence factor or patterning mediator, acting to regulate a variety of key tissue and cell identity genes, such as srp for the fat body and ladybird for the segment border muscle founder cells. Different target genes would be regulated in different locations by the combinatorial action of Six4 and other factors involved in dorsoventral and anteroposterior axis patterning. Six4 may play additional roles later in gonad development, since its expression is maintained in SGPs throughout embryogenesis, whereas it is expressed transiently in most of the mesoderm (Clark, 2006).

Defective Six4 function results partly in failure of cell fate maintenance and/or cell survival. This is a common mutant phenotype of members of the Six and Eya gene families. Strikingly, however, expression of Six4 with its cofactor, Eya, throughout the mesoderm causes the expansion of Six4-dependent cell types (fat body and SGPs) with the concomitant disruption of other mesodermal derivatives, including the cardioblasts and visceral mesoderm. This supports an active role for Six4 in initial patterning of cell fates. It is possible, therefore, that maintenance/survival phenotypes are a secondary effect of defects in the initial establishment of cell identity (Clark, 2006).

Specific aspects of muscle cell identity are affected in Six4 mutant embryos. The phenotype is variable, but the external lateral and some ventral muscles are consistently disrupted. When Six4 and Eya are misexpressed/overexpressed in the mesoderm, an aberrant but regular muscle pattern is formed, suggesting that they have a patterning role, as opposed to a function in differentiation or myoblast fusion. It is likely that Six4 participates in the activation of certain muscle identity genes in founder myoblasts. Expression of the SBM identity gene, ladybird, requires Six4, while misexpression of Six4 and eya specifically in founder cells (using a dumbfounded-Gal4 driver) results in a muscle phenotype indistinguishable from that of embryos misexpressing these genes throughout the mesoderm (Clark, 2006).

The relationship between Six4 and tin is complex, partly because it changes over time and also because tin has functions in the ventral and lateral mesoderm that have remained obscure. The best characterized functions of tin concern the dorsal mesoderm, reflected in its restricted dorsal expression at stage 10/11. At this time, Six4 expression is complementary to that of tin, and there are no discernable effects on dorsal mesoderm structures in Six4 mutants. It is proposed that these two genes play complementary roles in their respective domains, promoting the development of specific cell types in conjunction with additional patterning factors. Despite their complementary expression patterns at this stage, there is no evidence that tin and Six4 are mutually antagonistic: although Tin can act as a repressor as well as an activator, there is no significant expansion of Six4 expression along the dorsoventral axis in a tin mutant and vice versa (unpublished data). It is more likely that, like tin, Six4 is directly regulated by dpp signaling (Clark, 2006).

In addition to dorsal mesoderm defects, tin mutant embryos show SGP, fat body and specific lateral and ventral muscle defects that presumably depend on its early pan-mesodermal expression. At least one tin function appears to depend on its regulation of Six4 in the early mesoderm before their mutually exclusive refinement of expression. Like Six4, tin is required for correct SGP development: a reduced number of SGPs appear at stage 11, and the number diminishes further until stage 13 when germ cell migration defects become apparent. However, the ventral expression of tin is lost before the SGPs are apparent, suggesting that another factor mediates its function in SGP development. Six4 may be this factor, since initially the two genes are transiently coexpressed broadly in the mesoderm, and Six4 expression is partly dependent on tin function. At this stage, Tin could be a direct transcriptional activator of Six4, since there are a number of sequences in the third intron that match the core E-box of the canonical Tin binding site (ACAAGTGG) (Clark, 2006).

The pattern of lateral and ventral muscle defects in embryos lacking Tin is different from that of Six4 mutants. Muscles affected by tin include LL1, LO1, VL3, VL4, and VT1, which do not require Six4 or Eya. Conversely, muscles that are severely affected by Six4 mutation appear normal in tin mutants, including VA3, the SBM, and the external lateral muscles LT1, LT2, LT3, and LT4. Based on these findings, it is proposed that muscles fall into at least three categories. The visceral, cardiac, and dorsal somatic muscles all require tin function directly through persistent dorsal tin expression. A second group, comprising a subset of ventral and lateral muscles, requires tin function via its transient pan-mesodermal expression, either directly or perhaps through unknown patterning mediators. A third group, a different subset of lateral and ventral muscles, is dependent on Six4/eya function and is not affected in tin single mutants, presumably because the reduced Six4 expression in these embryos is sufficient for their patterning. Muscles in this last category resemble the fat body precursors in their functional requirements, being dependent on an early, partially redundant function of tin and zfh-1, which is necessary to initiate Six4 expression in most parasegments. Confirmation of this model awaits a comprehensive characterization of muscle identity gene expression in founder cells in tin and Six4 mutant embryos (Clark, 2006).

The role of Six4 in mesoderm patterning appears to be conserved in other organisms. Expression of human SIX5 is reduced in Type I Myotonic Dystrophy (Fillipova, 2001; Klesert, 1997; Thornton, 1997), which may suggest a role in myogenesis since the most severe forms of this condition display muscle developmental defects (Harper, 1989). The murine orthologues, Six4 and Six5, are both expressed during myogenesis (Oliver, 1995; Ozaki, 2001), although their precise roles are not yet established as single gene knock-out models have no clear muscle defects, perhaps owing to compensatory interactions (Klesert, 2000; Ozaki, 2001; Sarkar, 2000). Six4 mutation, however, strongly exacerbates the muscle loss of mice mutant for the more divergent homologue, Six1 (Grifone, 2005). It is striking in particular that hypaxial progenitors (which contribute to limb muscles) lose their identity in Six1 Six4 double mutant mice (Grifone, 2005). These muscle progenitors require the function of an lb homologue, Lbx1, and there is evidence that Lbx1 may be a target of Six/Six4 (Grifone, 2005). Thus, it appears that the function of Six4/5 genes might be conserved to a high degree (Clark, 2006).

The requirement for Six4 in diverse cell types, linked by their location of origin during mesoderm patterning, may represent a primordial state. The C. elegans homologue (unc-39) is also required for a number of mesodermal cell types (Yankowitz, 2004). Although knowledge of Six4 and Six5 function is incomplete, it is notable that Six1 is required for the development of diverse organs such as muscle, kidney, and otic vesicle. It is interesting to note that Lbx1 regulation may be achieved by the combinatorial action of Six1/4 and Hox genes (Alvares, 2003), which would thus behave as patterning factors in a similar way to Six4. The current studies suggest that diverse roles of SIX genes in vertebrate organogenesis as apparent cell- or tissue-type regulators may have their evolutionary origins in a general primordial developmental patterning mechanism, part of which may be preserved more clearly in the role of Six4 in mesoderm development in Drosophila (Clark, 2006).

Live imaging of Drosophila gonad formation reveals roles for Six4 in regulating germline and somatic cell migration

Movement of cells, either as amoeboid individuals or in organised groups, is a key feature of organ formation. Both modes of migration occur during Drosophila embryonic gonad development, which therefore provides a paradigm for understanding the contribution of these processes to organ morphogenesis. Gonads of Drosophila are formed from three distinct cell types: primordial germ cells (PGCs), somatic gonadal precursors (SGPs), and in males, male-specific somatic gonadal precursors (msSGPs). These originate in distinct locations and migrate to associate in two intermingled clusters which then compact to form the spherical primitive gonads. PGC movements are well studied, but much less is known of the migratory events and other interactions undergone by their somatic partners. These appear to move in organised groups like, for example, lateral line cells in zebra fish or Drosophila ovarian border cells. This study used time-lapse fluorescence imaging to characterise gonadal cell behaviour in wild type and mutant embryos. The homeodomain transcription factor Six4 is required for the migration of the PGCs and the msSGPs towards the SGPs. A likely cause of this was identified in the case of PGCs; Six4 is required for expression of Hmgcr which codes for HMGCoA reductase and is necessary for attraction of PGCs by SGPs. Six4 affects msSGP migration by a different pathway, since these move normally in Hmgcr mutant embryos. Additionally, embryos lacking fully functional Six4 show a novel phenotype in which the SGPs, which originate in distinct clusters, fail to coalesce to form unified gonads. This work establishes the Drosophila gonad as a model system for the analysis of coordinated cell migrations and morphogenesis using live imaging and demonstrates that Six4 is a key regulator of somatic cell function during gonadogenesis. The data suggest that the initial association of SGP clusters is under distinct control from the movements that drive gonad compaction (Clark, 2007; full text of article).

Drosophila homolog of the myotonic dystrophy-associated gene, SIX5, is required for muscle and gonad development

SIX5 belongs to a family of highly conserved homeodomain transcription factors implicated in development and disease. The mammalian SIX5/SIX4 gene pair is likely to be involved in the development of mesodermal structures. Moreover, a variety of data have implicated human SIX5 dysfunction as a contributor to myotonic dystrophy type 1 (DM1), a condition characterized by a number of pathologies including muscle defects and testicular atrophy. However, this link remains controversial. This study investigated the Drosophila gene, Six4, which is the closest homolog to SIX5 of the three Drosophila Six family members. This study shows by mutant analysis that Six4 is required for the normal development of muscle and the mesodermal component of the gonad. Moreover, adult males with defective Six4 genes exhibit testicular reduction. It is proposed that Six4 directly or indirectly regulates genes involved in the cell recognition events required for myoblast fusion and the germline:soma interaction. While the exact phenotypic relationship between Drosophila Six4 and mammalian SIX4/5 remains to be elucidated, the defects in Drosophila Six4 mutant flies suggest that human SIX5 should be more strongly considered as being responsible for the muscle wasting and testicular atrophy phenotypes in DM1 (Kirby, 2001; full text of article).

Six class homeobox genes in Drosophila belong to three distinct families and are involved in head development

The vertebrate Six genes are homologues of the Drosophila homeobox gene sine oculis (so), which is essential for development of the entire visual system. This study describes two new Six genes in Drosophila, Six3 and Six4, which encode proteins with strongest similarity to vertebrate Six3 and Six4, respectively. In addition, the partial sequences of 12 Six gene homologues from several lower vertebrates is reported and show that the class of Six proteins can be subdivided into three major families, each including one Drosophila member. Similar to so, both Six3 and Six4 are initially expressed at the blastoderm stage in narrow regions of the prospective head and during later stages in specific groups of head midline neurectodermal cells. Six3 may also be essential for development of the clypeolabrum and several head sensory organs. Thus, the major function of the ancestral Six gene probably involved specification of neural structures in the cephalic region (Seo, 1999; full text of article).

To investigate the functional roles of Drosophila Six3 and Six4, their expression patterns throughout embryogenesis were analyzed by whole-mount in situ hybridization. Transcripts of both genes are first detectable in the anterior region of early cellular blastoderm stage embryos, suggesting important roles in head development. In the case of Six3 expression is observed within a sharply defined circumferential stripe at approximately 85%-95% egg length (EL). The stripe is somewhat wider dorsally (~6 cells) than ventrally (~4 cells). Also expression levels are higher on the dorsal side of this domain from which several head structures derive (Seo, 1999).

The Six4 gene is initially expressed in a dorsal patch that straddles the midline between 85 and 90% EL. This patch is wider dorsally (3-4 cells) than towards its lateral edges. Hence, at the cellular blastoderm stage, Six4 appears to be expressed within a subregion of the Six3 expression domain. Interestingly, the Six4 expression pattern is also similar to that of so, which is expressed in a dorsal domain of the head region during the blastoderm stage. However, the area of so expression is located in a more posterior position where the primordia of the optic lobe, Bolwig's organ and eye disc are located (Seo, 1999).

Based on a projection onto the blastoderm fate map, Six3 is probably expressed in regions that will give rise to the clypeolabrum, pharynx and the anterior part of the acron. Hence Six3 and Six4 are apparently co-expressed in parts of the procephalic neurectoderm from which the brain originates. This conclusion is partly based on comparisons with the expression pattern of the gap gene tailless (tll). Like Six3, tll is expressed within a circumferential band at 76%-89% EL from which the procephalic proneural domain is thought to be derived. In accordance with the apparent overlap (~5%) in expression relative to tll, the Six3 (and Six4) positive area is likely to include only an anterior part of this proneural region (Seo, 1999).

During gastrulation and germ band elongation, Six3 continues to be expressed in the cephalic region but the pattern becomes more complex. The area and level of expression are increased dorsally, whereas the expression fades ventrally and disappears before stage 9. After initiation of stomodeal invagination, the expression domain is separated into two major subdivisions and this correlates spatiotemporally with the appearance of the clypeolabrum as a distinct part of the procephalic lobe. The clypeolabral expression domain at the anterior end is quite uniformly stained with sharply defined borders. Further posteriorly, the labeled area, which maps mainly to the procephalic neurogenic region, has more complex features, and is connected with the clypeolabral domain dorsally. Within this procephalic region the staining is distributed along the dorsal midline and in two bilaterally paired areas, with the highest signal intensity in the domains closest to the midline (Seo, 1999).

As the germ band retracts during stage 12, expression is maintained in the clypeolabral region and in two bilateral areas associated with the newly formed supra-oesophageal ganglia. Simultaneously, additional sites of expression become detectable ventrally in the maxillary and labial segments. Weaker expression is also present dorsolaterally in two small cell clusters located in the region which includes the optic lobe and dorsal ridge primordia (Seo, 1999).

By stage 13-14, when the germ band is fully retracted, parts of the clypeolabrum that express Six3 have invaginated through the stomodeum and contribute to form the roof of the pharynx. This staining extends posteriorly towards the supra-oesophageal ganglia where the expression is most conspicuous. The strongest expression is present in the medial parts of the supra-oesophageal ganglia and in a patch of cells in front of the brain which probably includes the frontal ganglion and the frontal connective of the stomatogastric nervous system (SNS). In addition to the clypeolabral expression, two distinct spots of staining are located ventral to the stomodeum. These apparently represent cells of head sensilla such as the terminal and labial organs that derive from the stained cell clusters detected at earlier stages in the maxillary and labial segments, respectively (Seo, 1999).

During head involution the clypeolabral staining also resolves into distinct spots and these may correspond to the labral sensory complex and the clypeolabral disc. Similarly, a refinement of the expression pattern occurs in the pharyngeal and supra-oesophageal regions. The staining in the roof of the pharynx becomes restricted to the area including the frontal ganglion and connective, while a row of cells just above it in the dorsal pouch shows high expression of Six3. Since only midline cells of the dorsal pouch are labeled, the eye-antennal disc precursors, which are known to be located in the lateral parts, probably do not express the Six3 gene. Expression is maintained in the dorsal pouch even after formation of the eye-antennal discs, in which staining is still not detectable at stage 18. Expression is also absent in the eye-antennal discs of 1st instar larvae and the transcript level is reduced in the frontal ganglia and connective, head sensory organs and clypeolabral derivatives. However, compatible with a possible involvement of Six3 in later stages of eye development, expression was detected in the eye-antennal discs of 3rd instar larva (Seo, 1999).

A recently reported Drosophila homeobox gene, optix, has also been shown to be expressed in restricted areas of the embryonic head during stages 5-11. Although only the homeobox is known for optix, the 100% nucleotide identity to Six3 and the similarity in expression patterns suggest that these two genes are the same (Seo, 1999).

As is the case for Six3, expression of the Six4 gene splits into two bilateral domains and persists in the dorsal part of the procephalic lobe during gastrulation and germ band elongation. By stage 9-10 transcripts are also detectable in mesodermal cells along the entire germ band. In a dorsal view the mesodermal staining appears to consist of a bilateral pair of longitudinal bands connected by a series of transverse stripes whose spacing corresponds to that of the segmental primordia. These features are consistent with the known transient segmental characteristics of the mesoderm at this embryonic stage. However, the mesodermal transcripts disappear quite rapidly and by stage 11 only the procephalic expression is detectable (Seo, 1999).

Coincident with germ band retraction and formation of the supra-oesophageal ganglion at stage 12, the two domains of dorsal Six4 expression narrow and lengthen, and during stage 13 they become associated with dorsal and medial parts of the two brain hemispheres. By stage 15 additional sites of expression are observed in the ventral cord and gonads (Seo, 1999).


REFERENCES

Search PubMed for articles about Drosophila Six4

Alvares, L. E., et al. (2003). Intrinsic, Hox-dependent cues determine the fate of skeletal muscle progenitors. Dev. Cell 5: 379-390. PubMed ID: 12967558

Clark, I. B., Boyd, J., Hamilton, G., Finnegan, D. J. and Jarman, A. P. (2006). D-Six-4 plays a key role in patterning cell identities deriving from the Drosophila mesoderm. Dev. Biol. 294(1): 220-31. PubMed ID: 16595131

Clark, I. B., Jarman, A. P. and Finnegan, D. J. (2007). Live imaging of Drosophila gonad formation reveals roles for Six4 in regulating germline and somatic cell migration. BMC Dev. Biol. 7: 52. PubMed ID: PubMed ID; Online text

Duan, H., Zhang, C., Chen, J., Sink, H., Frei, E. and Noll, M. (2007). A key role of Pox meso in somatic myogenesis of Drosophila. Development 134: 3985-3997. PubMed ID: PubMed ID; Online text

Fillipova, G. N., et al. (2001). CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat. Genet. 28: 335-343. PubMed ID: 11479593

Grifone, R., et al. (2005). Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo, Development 132: 2235-2249. PubMed ID: 15788460

Harper, P. S. (1989). Myotonic Dystrophy, W.B. Saunders Company.

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. PubMed ID: PubMed ID; Online text

Klesert, T. R., et al. (1997). Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP. Nat. Genet. 16: 402-406. PubMed ID: 9241282

Klesert, T. R., et al. (2000). Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat. Genet. 25: 105-109. PubMed ID: 10802667

Oliver, G., et al. (1995). Homeobox genes and connective tissue patterning, Development 121: 693-705. PubMed ID: 7720577

Ozaki, H., et al. (2001). Six4, a putative myogenin gene regulator, is not essential for mouse embryonal development. Mol. Cell. Biol. 21: 3343-3350. PubMed ID: 11313460

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. PubMed ID: PubMed ID; Online text

Thornton, C. A., et al. (1997). Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nat. Genet. 16: 407-409. PubMed ID: 9241283

Yankowitz, J. L., et al. (2004). UNC-39, the C. elegans homolog of the human myotonic dystrophy-associated homeodomain protein Six5, regulates cell motility and differentiation. Mech. Dev. 272: 389-402. PubMed ID: 15282156


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date revised: 20 March 2008

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