InteractiveFly: GeneBrief

lateral muscles scarcer: Biological Overview | References

Gene name - lateral muscles scarcer

Synonyms -

Cytological map position - 57A5-57A5

Function - Homeodomain transcription factor

Keywords - identity factor for lateral transverse muscles

Symbol - lms

FlyBase ID: FBgn0034520

Genetic map position - chr2R:16444364-16447458

Classification - homeodomain

Cellular location - nuclear

NCBI link: Precomputed BLAST | EntrezGene
lms orthologs: Biolitmine

Patterning and differentiation of developing musculatures require elaborate networks of transcriptional regulation. In Drosophila, significant progress has been made into identifying the regulators of muscle development and defining their interactive networks. One major family of transcription factors involved in these processes consists of homeodomain proteins. In flies, several members of this family serve as muscle identity genes to specify the fates of individual muscles, or groups thereof, during embryonic and/or adult muscle development. This study reports on the expression and function of a new Drosophila homeobox gene during both embryonic and adult muscle development. The newly described homeobox gene, termed lateral muscles scarcer (lms), which has yet uncharacterized orthologs in other invertebrates and primitive chordates but not in vertebrates, is expressed exclusively in subsets of developing muscle tissues. In embryos, lms is expressed specifically in the four lateral transverse (LT) muscles and their founder cells in each hemisegment, whereas in larval wing imaginal discs, it is expressed in myoblasts that develop into direct flight muscles (DFMs), which are important for proper wing positioning. The regulatory inputs of various other muscle identity genes with overlapping or complementary expression patterns towards the cell type specific regulation of lms expression were analyzed. Further it was demonstrate that lms null mutants exhibit reduced numbers of embryonic LT muscles, and null mutant adults feature held-out-wing phenotypes. A detailed description is provided of the pattern and morphology of the direct flight muscles in the wild type and lms mutant flies by using the recently-developed ultramicroscopy, and it was shown that, in the mutants, all DFMs are present and present normal morphologies. This study has identified the homeobox gene lms as a new muscle identity gene and shows that it interacts with various previously-characterized muscle identity genes to regulate normal formation of embryonic lateral transverse muscles. In addition, the direct flight muscles in the adults require lms for reliably exerting their functions in controlling wing postures (Müller, 2010).

The musculatures in both vertebrate and invertebrate animals are composed of a large variety of different muscles that are distinguished according to their specific size, morphology, and physiological properties. Whereas much progress has been made in defining the regulatory processes of myogenesis as such, the understanding of the developmental mechanisms underpinning muscle diversity is much less complete. To date, the fruit fly Drosophila has been one of the most profitable models for dissecting the mechanisms regulating muscle diversity. In this system, a number of mechanisms that provide specific identities to individual muscles have been described, particularly for the development of larval muscles during embryogenesis. By contrast, knowledge about the diversification of adult muscles, which takes place in a second round of muscle development during metamorphosis, is still much more limited (Müller, 2010).

Larval muscle development in Drosophila leads to the formation of ~30 distinct muscle fibers arranged in a stereotyped pattern within each embryonic trunk hemisegment. A large body of evidence has revealed that each of these muscles is seeded by a single myoblast, termed muscle founder cell, which already retains a defined identity that predetermines the characteristics of the particular muscle it will form. Upon myoblast fusion between founder myoblasts and fusion-competent myoblasts, which largely lack distinct identities, the identity of the founder cell is then imposed on the growing muscle syncytium and shapes its development. In the current view, the identity of individual founder cells is conferred through the expression and function of particular combinations of muscle identity genes. The muscle identity genes that have been characterized functionally to date all encode various types of transcription factors. The best-characterized muscle identity factors belong to the families of the homeodomain proteins (including Apterous/Ap, Slouch/S59, Ladybird/Lb, Even-skipped/Eve), Zinc-finger factors (Krüdppel/Kr), basic helix-loop-helix factors (Nautilus/Nau), and the COE (Col/Olf1/EBF) transcription factors (Collier/Col). In addition, the activities of these identity factors are modulated by transcription factors that are expressed within distinct broad domains in the somatic mesoderm, such as the homeodomain proteins Tinman/Tin, Muscle segment homeodomain/Msh, Six4, and Pox meso. Another notable example of this latter class of regulators are the Hox factors, which are expressed in broad domains along the anterior-posterior axis within the somatic mesoderm and are known to modulate the activities of muscle identity factors in a region-specific manner along this axis. As has been shown in some of these cases, different muscle identity genes and regional regulators are part of hierarchical and cross-regulatory networks during the development of a particular muscle. As a result, some of the identity factors and regional factors are expressed only transiently whereas the expression of others continues until a mature fiber is formed. Ultimately, the functions of these transcription factors in muscle fate determination must be mediated by their transcriptional target genes, but information about these targets and their roles in making muscles distinct is currently rather limited (Müller, 2010).

During metamorphosis, the majority of the adult muscles are generated anew from the descendants of undifferentiated myoblasts, termed adult muscle precursors, that are set aside during embryogenesis and start proliferating during larval stage. Currently, there is no clear evidence for muscle identity genes acting at the level of individual muscle founder cells during adult muscle development. However, like in embryos, Hox genes are known to play an important role during the regional diversification of muscle patterns along the anterior-posterior axis. Another example for genes involved in adult muscle diversification is ladybird, which is widely expressed in leg disc-associated myoblasts and required for normal leg muscle development. Hence, this embryonic muscle identity gene is redeployed during metamorphosis to participate in the control of the development of large subset of myoblasts, namely those forming the leg muscles. An instructive example of myoblast diversification during metamorphosis has also been described in the wing disc. The wing disc-associated myoblasts generate two fundamentally different types of muscles, which on the one hand include the indirect flight muscles that power the flight, and on the other hand the direct flight muscles that control wing positioning during steering and flight stabilization. It has been demonstrated that the myoblasts giving rise to the indirect flight muscles (IFMs), which form the majority of the wing disc-associated myoblasts and are located in proximal areas of the wing disc of the presumptive notum, are marked by the expression of the homeobox gene vestigial/vg. Conversely, the myoblasts forming the direct flight muscles (DFMs), which are located in adjacent areas near the future wing hinge, are marked by high-level expression of the homeobox gene cut. In this latter population of myoblasts, high levels of Cut repress vestigial, whereas in the IFM-forming population of myoblasts Vg down-regulates cut to low expression levels. In addition, Vg represses apterous (ap), which can therefore only be activated in the high-cut myoblasts. ap then helps specifying these myoblasts as DFM myoblasts. Altogether, these regulatory interactions and the functions ascribed to vg and cut/ap in IFM versus DFM development point to some mechanistic analogies of muscle diversification during larval and adult muscle development (Müller, 2010).

As the currently-known collection of muscle identity genes is still not sufficient to explain the entire muscle pattern during embryogenesis, and even less so during formation of adult muscle diversity, these studies have been aiming to identify additional genes of this type. This report describe a new homeobox gene, lateral muscles scarcer (lms), that fulfills the criteria for a muscle identity gene. During embryogenesis, lms is expressed specifically in the founders and syncytial fibers of the lateral muscles LT1-LT4 as part of a regulatory network that includes ap, which exhibits a closely related expression pattern, as well as lb, Kr, and msh. Null mutations for lms, which are homozygous viable, cause defects in LT muscle development that consist of a reduction in the number of muscles and morphological aberrations. These defects occur with a relatively low expressivity, similar to those reported for ap, and double mutants for lms and ap show additive effects. During adult muscle development, lms is expressed in wing disc-associated myoblasts within a small area that overlaps with the presumptive DFM myoblasts marked by high-cut expression. The held-out wing phenotype of lms null mutant flies is compatible with a requirement of lms for normal DFM differentiation. Because detailed analysis of the DFMs in lms mutant flies showed that the DFMs are present and lack any overt morphological alterations, it appears that lms is needed for the acquisition of the requisite functional properties of these muscles rather than their formation and morphogenesis (Müller, 2010).

Homeobox gene lms is the first representative among its orthologs in insects and primitive chordates (Ciona and amphioxus) that has now been characterized in terms of its expression and function. Although some expression data are available for Nkx-C, its ortholog from Ciona intestinalis, the exact tissues of expression of this gene remain to be characterized (Satou, 2008). Of note, in Drosophila the expression of lms is highly restricted and only found in specific domains of cells within the somatic mesoderm and the muscles derived from them. The lms gene is active within the somatic mesoderm during both larval and adult myogenesis, which suggested that it functions during both of these phases of muscle development (Müller, 2010).

In the embryo, lms is expressed like a typical muscle identity gene. Its expression in progenitors, founders and syncytia of the lateral muscles LT1 - LT4 is very similar to the mesodermal expression of the LIM homeobox gene apterous (ap), except that ap is activated slightly earlier in the corresponding myogenic preclusters. ap exerts regulatory inputs towards lms, which become most apparent upon ectopic expression of ap. However in ap mutants, lms is still expressed largely normally and the same is true for the expression of ap in lms mutants. Thus, although regulatory interactions between the two genes do exist, their expression seems to be established largely independently from one another by related upstream activators. Two candidates for these include msh and lb. msh expression is significantly broader but overlaps with lms, and loss of msh function causes delayed and less robust lms expression. Conversely, lb is expressed in adjacent cells and appears to play a role in the spatial restriction of lms expression. Because single mutations for any of the tested candidate genes do not lead to a total disruption of lms expression, either these regulators act redundantly or there are additional yet unidentified regulators of lms expression that play more indispensable roles (Müller, 2010).

Loss of lms can cause the absence of individual LT muscles or in some cases morphological changes, particularly insertions into inappropriate attachment sites. The absence of an LT muscle could be due to a transformation of its identity into another, although no clear examples of that have been observed. Alternatively, loss of lms function could lead to a failure of a muscle founder to acquire any specific identity or to progress only partially towards acquiring a normal LT muscle identity. This second interpretation, which is compatible with the occasional presence of a small, amorphous syncytium at the position of a missing fiber and the observation of mis-attached and mis-shapen LT muscle fibers, is favored. Interestingly, similar phenotypes with comparable low expressivity were also described for ap mutants. To explain the low expressivity, it was proposed that additional factors can partially compensate for the loss of ap function. Because the expression of lms in LT muscles and their progenitors is very similar to that of ap, Lms was a very good candidate for such a factor. However, in ap, lms double mutants the majority of LT muscles are still present as well, thus ruling out that the two genes are required for LT muscle specification in a mutually-redundant fashion. Rather, the roughly additive effects on the expressivity in the double mutants indicate that the two genes act in parallel with each other and in combination with yet other, perhaps more critical genes during the specification of LT muscle identities. These likely include Kr and msh, functional loss of which leads to a loss of over 30% and 50% of the LT muscles, respectively, as well as yet unknown genes (Müller, 2010).

Altogether, it appears that lms (and ap) is needed for securing the robustness of the program determining LT muscle identities. The findings reinforce the view that there is a significant degree of redundancy built into the muscle specification program in Drosophila. It is increasingly clear that the expressivities of phenotypes upon loss of function of different muscle identity genes occupy a wide range. Whereas lms and ap fall into the low end of this range, the expressivity of msh and Kr phenotypes is low for some muscle lineages and intermediate for others. At the high end of this spectrum are mutations for slou, col, and eve, which affect essentially all muscle lineages in which these identity genes are expressed. In addition, it must be considered that identity genes act within a hierarchically structured network of interactions and at different steps of muscle development. Some of them (e.g., slou, eve, lb) appear to have major roles during the initial diversification of founder cells, whereas others (e.g. ap, lms) may act mainly or purely in the execution of identity programs of specified muscle precursors and the acquisition of individual muscle features such as shape, attachment, and distinct functional properties (Müller, 2010).

The presence of a wing posture phenotype in almost all lms mutant flies, albeit with variable severity, argues for a rather strict requirement for lms during adult muscle differentiation. The major domain of expression during this phase occupies the area of wing disc-associated myoblasts marked by high-cut expression that give rise to the direct flight muscles (DFMs). Interestingly, ap is also activated in these cells, but unlike in embryos, in this case significantly later than lms, namely in pupal stages. Reduction of ap activity has been shown to severely disrupt the formation of DFMs. By contrast, all DFMs are formed and are arranged normally in lms null mutants, which implies that lms is not required for DFM muscle specification and morphogenesis. Instead, it is presumed that lms is needed in these muscles to fulfill their proper functions, which include the adjustment of wing positions and steering during flight. It is conceivable that ap acts together with lms in this pathway, even though ap has additional roles in regulating the formation or survival of DFMs. Only the lms mutant flies with mild or absent held-out wings phenotypes are able to fly, but their steering behaviour, which still may be disrupted, has not been examined. As shown in this study, loss of lms leads to ectopic expression of vg in the presumptive DFM myoblasts. This effect could in part explain the functional defects of the resulting DFMs since GAL4/UAS-driven vg is known to interfere with normal DFM development. In this study, 1151-GAL4-driven vg caused the reported held-out wing phenotype but, as with lms mutants, analysis of these flies via ultramicroscopy did not reveal any differences in the DFM muscle pattern. Whereas most genes with held-out or held-up wing phenotypes encode various muscle proteins, a few others such as Dichaete and mirror are expressed in proximal areas of the disc epithelium and, when mutated, cause disruptions of wing structures in the hinge region. By contrast, lms mutants with held-out wings show normal morphologies of proximal wing elements, which together with the myoblast-specific expression pattern of lms reinforces the notion of a DFM-specific role of lms (Müller, 2010).

A similar held-out wing phenotype as for lms and ectopic vg has been observed for Wnt2 mutant flies, which show a loss, mis-attachment, or ectopic location of usually several of the DFMs in each fly. Presumably as a result of these DFM patterning or attachment phenotypes, Wnt2 mutant flies hold out their wings more strongly as compared to lms mutants and are also unable to fly. The late expression at the epidermal wing hinge of Wnt2 and its temporal requirement, which occurs only during pupariation, rules out a role of Wnt2 in inducing lms, which is already expressed during third instar. However, it remains to be examined whether Wnt2 is needed for the maintenance of lms expression (and/or induction of ap) in the developing DFM myoblasts, which would be analogous to the known role of Wingless in the maintenance of vg in the presumptive indirect flight muscle (IFM) myoblasts (Müller, 2010).

Drosophila araucan and caupolican integrate intrinsic and signalling inputs for the acquisition by muscle progenitors of the lateral transverse fate

A central issue of myogenesis is the acquisition of identity by individual muscles. In Drosophila, at the time muscle progenitors are singled out, they already express unique combinations of muscle identity genes. This muscle code results from the integration of positional and temporal signalling inputs. This study identified, by means of loss-of-function and ectopic expression approaches, the Iroquois Complex homeobox genes araucan and caupolican as novel muscle identity genes that confer lateral transverse muscle identity. The acquisition of this fate requires that Araucan/Caupolican repress other muscle identity genes such as slouch and vestigial. In addition, Caupolican-dependent slouch expression depends on the activation state of the Ras/Mitogen Activated Protein Kinase cascade. This provides a comprehensive insight into the way Iroquois genes integrate in muscle progenitors, signalling inputs that modulate gene expression and protein activity (Carrasco-Rando, 2011).

The study of myogenesis in Drosophila has increased the understanding of how the mechanisms that underlie the acquisition of specific properties by individual muscles are integrated within the myogenic terminal differentiation pathway. Thus, the current hypothesis proposes that distinct combinations of regulatory inputs leads to the activation of specific sets of muscle identity genes in progenitors that regulate the expression of a battery of downstream target genes responsible for executing the different developmental programmes. However, the analysis of the specific role of individual muscle identity genes and of their hierarchical relationships is far from complete since the characterisation of direct targets for these transcriptional regulators is very scarce (Carrasco-Rando, 2011).

ara and caup, two members of the Iroquois complex, have been identified as novel type III muscle identity genes. The homeodomain-containing Ara and Caup proteins are necessary for the specification of the lateral transverse (LT) fate. ara/caup appear to be bona fide muscle identity genes. Indeed, similarly to the identity genes Kr and slou, absence of ara/caup does not interfere with the segregation of muscle progenitors or their terminal differentiation, but modifies the specific characteristics of LT1-4 muscles, which are transformed towards VA1, VA2, LL1 and LL1 sib fates. These transformations may be due in part to the up-regulation of slou and vg in the corresponding muscles. Thus, a recent report (Deng, 2010) shows that forced expression of vg in LT muscles induces changes in muscle attachments similar to the ones observed in LT1 in ara/caup mutant embryos. However, it should be stressed that although in ara/caup mutants LT muscles are lost in more than 95% of cases, they are not completely transformed into perfect duplicates of the newly acquired fates. For instance, while the specific LT marker lms is lost in 91% of cases, ectopic slou expression is detected in only 75% of cases. These partial transformations might be due to differences in the signalling inputs acting in the mesodermal region from where these muscles segregate. Unpublished data also showed that forced pan-mesodermal expression of ara/caup alter the fates of many muscles both in dorsal and in ventral regions without converting them into LT muscles (i.e., they do not ectopically express lms). Similarly, Kr and slou ectopic expression is not sufficient to implement a certain muscle fate. The failure to recreate a given muscle identity by adding just one of the relevant muscle identity proteins reveals the importance that cell context, that is, the specific combination of signalling inputs and gene regulators present in each cell, have in determining a specific muscle identity (Carrasco-Rando, 2011).

Analysis of the myogenic requirement of ara/caup has revealed several features about how these genes act to implement LT fates. Thus, although they are expressed in six developing embryonic muscles, only four of them, LT1-4, are miss-specified in the absence of Ara/Caup. The remaining two, DT1 and SBM, seem to develop correctly, according to morphological as well as molecular criteria. It is worth noting that the requirement for ara/caup genes in these six muscles correlates with the onset of their expression. Thus, in the affected LT1-4 muscles Ara/Caup can be first detected at the earliest step of muscle lineages, that is in the promuscular clusters. In contrast, in the unaffected muscles ara/caup start to be expressed later, in the DT1/DO3 progenitor and the SBM founder. This suggests that in muscle lineages ara/caup have to be expressed very early to repress slou and vg to implement the LT fate. Several data support this interpretation. For instance, the observation that ara/caup are co-expressed with slou in DT1, whereas they repress slou in LT3-4, may be related to the fact that slou expression precedes that of ara/caup in the DT1 lineage. Should this be so, one would expect that ectopic expression of ara using the early driver mef2-GAL4, would repress slou in DT1, as it actually does, whereas this repression is not evident using the late driver Con-GAL4. Furthermore, the hypothesis of the relevance of the timing of muscle identity gene expression for muscle fate specification might also apply to the case of slou, where a similar correlation between the strength of the loss-of-function slou phenotypes in specific muscles and the onset of slou expression has also been found (Carrasco-Rando, 2011).

It should be stressed that the generation of the LT code depends not only on the early presence of Ara/Caup on the promuscular clusters but also on the absence (or strong reduction) of DER/Ras activity at that precise developmental stage and location. There is a dynamic regulation of MAPK signalling in the lateral mesoderm. Caup-expressing muscles develop from DER-independent clusters whereas the duplicated muscles observed in ara/caup mutants derive from progenitors that segregate very near the LT progenitors, but originate in DER-dependent promuscular clusters that are specified slightly later in development. Furthermore it was observed both by in vivo and in cell culture that low MAPK activity is required for Caup-dependent slou repression. Therefore, the role of Ara/Caup in the implementation of LT fate is interpreted as follows. At mid stage 11 in the myogenic mesoderm, groups of mesodermal cells acquire myogenic competence as a result of interpreting a combinatorial signalling code that reflects their position along the main body axes, as well as the state of activation of different signalling pathways. Accordingly, these clusters initiate the expression of lethal of scute and a unique code of muscle identity genes, as has been shown in great detail for eve expression in the dorsal mesoderm. In the case of the dorso-lateral mesoderm this code includes ara/caup and Kr and implements the LT fate. Since the level of activation of the Ras/MAPK cascade is low in these clusters, Ara/Caup will behave as transcriptional repressors, preventing the activation of slou or vg in LT1-2 and LT3-4 clusters, which would be otherwise activated in this location. Thus, Ara/Caup implement the LT fate by repressing the execution of the alternative fates (Kr+, Slou+, Con+, Poxm+ and Kr+, Vg+) that would give rise to duplicates of PVA1/VA2 and PLL1/LL1sib, respectively, and by allowing a different identity gene code (Kr+, Caup+, Con+, lms+) that generates the LT fate (Carrasco-Rando, 2011).

Slightly later the Ras/MAPK pathway becomes active at the dorsolateral region. This changes the combinatorial signalling code and coincides with a change in the muscle identity genes expressed by the promuscular clusters that segregate from this position, which now accumulate Kr but not Ara/Caup. Progenitors born from them will express either slou or vg and give rise to VA1-2 and LL1/LL1sib fates, all DER-dependent (Carrasco-Rando, 2011).

The data suggested that Ara/Caup might act as repressors of slou in the Drosophila mesoderm. Therefore whether slou might be a direct target of Ara/Caup was investigated. An 'in silico' search of a previously reported slou cis-regulatory region identified two putative Iro binding sites (BS) at positions +129 (BS1) and -1642 (BS2), relative to the transcription start site, which match the consensus ACAN2-8TGT. This regulatory region was cloned in a Luciferase reporter vector and Luciferase activity was measured in Drosophila Schneider-2 (S2) cells transiently transfected with this construct and increasing amounts of HA-tagged Caup. Contrary to expectations, it was found that addition of Caup-HA increased the basal Luciferase activity driven by the slou regulatory region in a dose dependent manner, indicating that Caup acts as a transcriptional activator of slou under these conditions. The reported regulation of the chicken Irx2 factor by MAPK (that switches it from repressor to activator) could explain this result. Since Western Blot analysis of S2 lysates using an antibody against diphospho-extracellular-signal related kinase (dpErk) showed the MAPK pathway to be active in S2 cells, and experimental evidence has been obtained showing the presence of phosphorylated Caup in S2 cells with constitutively active MAPK pathway, it was hypothesized that the activation effect of Caup in S2 cells could be due to the Ras/MAPK cascade turning Caup from transcriptional repressor into activator. Indeed, the inhibition of the Ras/MAPK pathway by the PD98059 MAP-erk kinase-1 (MEK1) inhibitor induced a Caup-dose dependent decrease in Luciferase activity driven by the slou regulatory sequences. This result could not be attributed to a direct effect of the inhibitor over the slou promoter, since its addition did not modify the basal Luciferase activity of the construct (Carrasco-Rando, 2011).

Thus S2 cell experiments suggest a molecular mechanism by which the Ras/MAPK pathway modulates the transcriptional activity of Ara/Caup on slou. Low MAPK activity and direct binding of Caup to BS1 site of the slou gene would favour strong repression of slou. BS1 could be embedded in a silencer regulatory element or its binding to Caup may block transcription of the downstream located luciferase gene. On the contrary, Caup-dependent activation of slou would be dependent on MAPK signalling. It is hypothesized that MAPK-dependent Caup phosphorylation could modulate its interaction with different transcriptional co-factors or/and its binding site affinity (Carrasco-Rando, 2011).

Furthermore, in vivo evidence indicates a repressor function of presumably non-phosphorylated Caup on slou since forced activation of the Ras pathway allows co-expression of slou and caup. On the other hand, the ectopic expression of slou induced by caup-over-expression is suggestive of a possible activator function of phosphorylated Caup (Carrasco-Rando, 2011).

The role of IRO proteins in cell fate specification is conserved in both vertebrates and invertebrates. This study has shown that the interplay between MAPK signalling and IRO activity found in vertebrate neuroepithelium is also at work in Drosophila myogenesis. This study has identified potential direct target of Ara/Caup, slou and has proposed vg as a candidate gene to be regulated by Ara/Caup. In both cases the genes subordinated to ara/caup encode transcription factors that might in turn regulate the expression of other genes, genes that must be repressed in LT muscles in order to acquire the LT fate. These results, therefore, provide insights into the way Ara/Caup control lateral muscle identity and on the role of signalling pathway inputs to modulate the activity of these transcription factors, with consequences in their downstream targets. It also highlights the importance that the specific combination of muscle identity genes, their hierarchical relationships and their temporal activation have in determining the identity of a given muscle cell, very alike to what is at work during the acquisition of neural fates (Carrasco-Rando, 2011).


Search PubMed for articles about Drosophila Lateral muscles scarcer

Carrasco-Rando, M., et al. (2011). Drosophila araucan and caupolican integrate intrinsic and signalling inputs for the acquisition by muscle progenitors of the lateral transverse fate. PLoS Genet. 7(7): e1002186. PubMed ID: 21811416

Deng, H., Bell, J. B. and Simmonds, A. J. (2010). Vestigial is required during late-stage muscle differentiation in Drosophila melanogaster embryos. Mol. Biol. Cell 21: 3304-3316. PubMed ID: 20685961

Müller, D., et al. (2010). Regulation and functions of the lms homeobox gene during development of embryonic lateral transverse muscles and direct flight muscles in Drosophila. PLoS One 5(12): e14323. PubMed ID: 21179520

Satou, Y., Wada, S., Sasakura, Y. and Satoh, N. (2008). Regulatory genes in the ancestral chordate genomes. Dev Genes Evol 218: 715-721. PubMed ID: 18773221

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date revised: 4 August 2012

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