myoblast city


In order to make a detailed analysis of the muscle phenotype of embryos mutant for mbc, an antibody against Drosophila muscle myosin was used to reveal the muscles during development. In wild-type embryos, muscle myosin is first expressed approximately 9 hours after egg laying (AEL). At this time, myoblast fusion is under way and every muscle is represented by a precursor. Myosin expression begins in a small number of precursors lying on the ventral and lateral sides of the mesoderm and rapidly extends to all the precursors and some of the cells that are about to fuse with them. By 13 hours AEL, the muscle pattern is complete and muscle attachments are forming on the epidermis. In embryos mutant for mbc, myosin expression begins on schedule, at 9 hours AEL, in cells that appear by their position to belong to the somatic mesoderm. Because of their position and muscle myosin expression, these cells are identified as myoblasts. As in the wild-type, expression begins in a few cells on the ventral and lateral sides of the mesoderm, and by 10 hours, apparently extends to most of the cells of the somatic mesoderm. The myosin-expressing cells are clearly organized into an array that resembles the pattern of wild-type muscle precursors, with a segmentally repeated arrangement of ventral, lateral and dorsal cell clusters. Strikingly, with only a few exceptions, these myoblasts fail to fuse. Initially, all the cells are rounded, but from 11 hours AEL, members of a subset of mononucleate cells become slightly elongated, lying in positions and orientations similar to the multinucleate muscle precursors in wild-type embryos. The elongated myoblasts first appear at about 11 hours AEL and increase in number until about 13-15 hours AEL. After this time some myoblasts become much longer, some now spanning distances two or three times the length of normal muscles. These myoblasts occasionally have more than one nucleus, indicating that a small number of cell fusions occur. At 13 hours AEL, there are still large numbers of rounded myosin-expressing myoblasts, but from 14 hours onward, this population diminishes. Some cells may simply lose myosin expression: using Nomarski optics, one may see many faintly stained and unstained rounded cells. However, cell death is also involved, because myosin-positive cells engulfed by macrophages can also be seen (Rushton, 1995).

Groovin is expressed in the epidermis at muscle attachment sites. To investigate whether or not the elongated myoblasts indeed find their correct attachment sites, embryos were double-labelled using anti-myosin and anti-Groovin. Myosin-positive cells stretch out and making contact with Groovin-positive epidermal cells, which appear normal in mbc mutant embryos. It is concluded that at least some of the elongated myoblasts succeed in forming attachments with appropriate cells in the epidermis, and that myoblast fusion is not required for the normal patterning of muscle attachment sites on the epidermis. In summary, there appear to be two populations of myoblasts within embryos mutant for mbc. Both populations are first visible by myosin expression at 9 hours AEL, as rounded cells, and one population remains rounded as long as they are detectable, decreasing in number from about 13 hours AEL. The other type of cells, in contrast, can be distinguished as elongated cells from about 11 hours AEL, often situated in positions and orientations recognizable for being like those of wild-type muscle precursors, and these cells continue to express myosin until at least 17 hours AEL, when cuticle formation prevents further antibody staining. Initially these cells are only slightly elongated, but from about 15 hours AEL they stretch and send out long processes. These two myoblast populations and their behaviours are reminiscent of the two myoblast types postulated to exist during wild-type myogenesis. The rounded myoblasts in mbc mutants might constitute the pool of myoblasts available for fusion, whereas the elongated cells might represent the founder cells, whose special properties are revealed in this mutant because fusion fails to occur (Rushton, 1995).

To explore this idea, and especially to explore the idea that founder cells represent a class of cells that organize and initiate the process of formation of the musculature, mbc mutant embryos were stained using antibodies against NK1 (S59) and Vestigial (Vg), the products of two genes that are expressed in putative founder cells. The early expression of S59 is identical in wild-type and mbc mutant embryos. S59 expression begins in a consistent pattern of a small number of cells in the somatic mesoderm. In both wild-type and mbc mutant embryos, expression begins in each abdominal hemisegment in a single ventral cell between 6 and 7 hours AEL; each cell divides to give rise to two cells, known collectively as Group I. Four cells posterior and slightly ventral to Group I begin expression at about 7 hours AEL; these are known as Group II. Group III is the last to appear, at about 8 hours AEL, consisting of two cells lying dorsal to the cells of Group II and at the same level in the anteroposterior axis as the cells of Group II. Subsequently, S59-expressing cells undergo movements and pattern refinements and this rearrangement is identical in mbc mutants and wild-type embryos, as the following will describe:

After Group I has divided into two cells, cell Ib remains in the same place, while cell Ia migrates across the segment border in both mbc mutants and the wild-type. The behaviour of Group II in mbc mutants appears at first sight to be different from that of the wild-type, in that only one of the original four cells maintains S59 expression after germ band retraction. In the wild-type, all the cells of Group II had been thought to maintain expression, contributing eventually to muscle 27. However, more recent observations (Carmena, Bate and Jimenez, unpublished data) show that in fact, only one of the cells of Group II does so. The other cells gradually lose S59 expression and each one contributes to a separate muscle. The loss of S59 expression in three of the four cells of Group II in mbc mutants, therefore, exactly follows the sequence of S59 expression in wild-type embryos. Group III also maintains S59 expression in only one cell in embryos mutant for mbc. Once again it is probable that this corresponds to events in the wild-type as it is likely that the two cells of Group III give rise to two separate muscles, only one of which (muscle 18) expresses S59 (Carmena, Bate and Jimenez, unpublished data). Oddly, cell Ib does behave abnormally in mbc. In wild-type embryos, cell Ib continues to express S59 and gives rise to muscle 25. In mbc mutants, however, cell Ib loses expression. This is all the more curious, because a putative founder cell for muscle 25 is seen in mbc mutant embryos that have been stained for myosin. In embryos mutant for mbc, therefore, the initial pattern of S59 expression is almost identical to wild-type, suggesting that the segregation and movement of founder cells is normal in these mutants. There is, however, a dramatic difference in S59 expression between wild-type and mbc mutant embryos, in that muscle fusion fails to occur in mbc mutants and there is no concomitant increase in the number of nuclei positive for S59. Thus, fusion is required for the recruitment of cells to express S59, as predicted by Dohrmann (1990). The S59-positive cells remain as single cells, lying in approximately the same position as the muscle they would normally have given rise to, and continue to express S59 at least until 17 hours AEL (the limit of the ability to detect protein by antibody staining). In 3% of cases (n=200), two cells can be seen instead of one and it is assumed that this is caused by the rare fusion events that occasionally take place in mbc mutant embryos (Rushton, 1995).

Like S59, vg is expressed in a small number of mesodermal cells. In the wild-type embryo, these cells contribute to ventral muscles 6, 7, 12 and 13, and dorsal muscles 1, 2, 3 and 4. Early development of the dorsal muscles is difficult to examine because vg expression in the epidermis overlies and partly conceals the dorsal mesodermal vg expression. Ventral mesodermal vg expression has been studied in detail. Ventrally, vg expression in wild-type and in mbc mutants begins in one cell per abdominal hemisegment during the extended germ band stage of development and soon increases to three or four cells. By 10 hours AEL, the cells lie in a small cluster in the posterior of the segment. So far, the pattern of vg expression is identical in wild-type and mbc mutant embryos. In wild-type, the vg-expressing cells further increase in number and resolve into four ventral longitudinal muscles. In mbc mutants, however, the vg-expressing cells do not increase in number, but otherwise behave in a similar fashion to the wild-type ones. The four cells separate and align themselves in a dorsoventral pattern in the positions normally taken by the ventral longitudinal muscles. Thus, it is possible to draw two conclusions: (1) that for S59 expression, increase in the number of vg-expressing cells is due to fusion and recruitment, and (2) that the vg-expressing cells contain the necessary information to migrate to their correct positions in the segment (Rushton, 1995).

The above results suggest that founder cells are segregated normally in mbc mutants and behave normally in every respect save that of fusion. To confirm that these cells correspond to the stretched myoblasts seen in the myosin-stained preparations, mbc mutants were double stained using antibodies to myosin and Vg or S59. In mbc mutants vg or S59 positive nuclei are clearly seen in stretched myosin-expressing cells that span the territory that, in wild-type, is occupied by an S59- or vg-expressing muscle. A vg- or S59-expressing nucleus with a rounded cytoplasm has never been seen. It is not always possible to see the cytoplasm of these cells owing to the many rounded myoblasts that surround them. However where the cytoplasm can be distinguished, the orientation of the cell is consistent with the orientation of the wild-type muscle that it represents. It is concluded, therefore, that myoblasts expressing S59 or vg contain information that enables them to find their correct position and orientation (Rushton, 1995).

A feature of normal Drosophila development is specific innervation of particular muscles by particular motor neurons. The Connectin protein is expressed on the surface of a subset of developing motor neurons and muscles and may be involved in mediating homophilic adhesion between them, prior to synapse formation. mbc mutant embryos were stained with an antibody to the Connectin gene product and this staining shows that a subset of myoblasts in the appropriate parts of the segment express Connectin on their surface, while the surrounding myoblasts do not. Moreover, Connectin-expressing myoblasts are contacted specifically by Connectin-expressing nerves. This strongly suggests that these Connectin-expressing myoblasts have an identity that is recognized by motor neurons and not shared by the surrounding pool of myoblasts (Rushton, 1995).

It is concluded that the phenotype of mbc mutants supports the founder cell hypothesis. There are indeed, in mbc mutants, two different populations of myoblasts: one that remains rounded throughout embryogenesis and one that becomes elongated. This apparent subdivision could be a result of random behaviour of the myoblasts, as a consequence of failure of fusion or some other aspect of the mbc mutant phenotype. However, in embryos mutant for mbc S59- and vg-expressing cells have been identified, along with the stretched myosin-expressing cells. For example, some vg-expressing cells have processes that span the region, which in wild-type would be spanned by vg-expressing muscles. The orientation of these single-cell 'muscles' is not always accurate, but this is most likely because these myoblasts explore their surroundings later than wild-type muscle precursors, and the surfaces over which they migrate may be expressing different proteins. Moreover, the unfused myoblasts themselves may make the terrain confusing to exploring cells. It is perhaps the more surprising therefore that so many of the founder cells that were see were in the correct orientation. In mbc mutants, S59- or vg-expressing cells appear at the correct time and place, and migrate correctly, but fail to recruit surrounding cells to S59 or vg expression, showing that the S59 and vg-expressing cells are a distinct population of myoblasts with their own identity. Clearly, as predicted by the founder cell hypothesis, neighboring myoblasts cannot acquire this identity in the absence of fusion. It seems clear that in mbc mutant embryos, Connectin is expressed on the surface of a subset of unfused myoblasts and on nerves making contact with these myoblasts. Therefore, these particular myoblasts must have an identity that can be recognized by the outgrowing motor axons, an identity not shared by the surrounding myoblasts. This observation is also consistent with the founder cell hypothesis, as it shows that only a subset of myoblasts are able to specify a characteristic pattern of innervation (Rushton, 1995).

Myoblasts in embryos homozygous for mutations in the myoblast city (mbc) gene fail to fuse, and form loose clusters of myosin-positive cells in locations roughly corresponding to the ventral, lateral, and dorsal muscle groups. Many single myoblasts are removed during dissection of the embryo unless great care is taken. The myoblasts express myosin robustly, and usually have the typical single pseudopodium seen in electron micrographs of normal myoblasts before alignment. Typical of mbc myoblasts is the nearly complete absence of prefusion complexes, consistent with the prefusion complex forming after recognition and/or adhesion of myoblasts to target cells. Although an occasional complex can be seen at apparently random locations, the number of prefusion complexes is reduced by at least 90%. The few prefusion complexes that do exist contain roughly wild-type numbers of paired vesicles, suggesting that the defect in mbc myoblasts lies upstream of the actual assembly of the prefusion complex. There are no electron dense plaques between myoblasts in mbc embryos. At both the light microscopic and EM level, mbc myoblasts do not appear to align and become elongated as wildtype myoblasts do. In electron micrographs of early stage 13 embryos, mbc myoblasts have characteristic teardrop morphology, with a single pseudopod per cell. However, there appears to be slightly more extracellular space between myoblast cell bodies in mbc embryos. By stage 14, there is no sign of specific attachment sites for unfused myoblasts, as is the case in embryos mutant for blown fuse, another gene involved in myoblast fusion, although clusters are present in the locations corresponding to the main muscle groups. It is hypothesized that the random orientation of myoblasts relative to pioneer cells is due to a failure of one of two processes, either target recognition or cell adhesion. By the end of stage 16, most unfused myoblasts have been cleared by macrophages, revealing a rough scaffolding of muscle pioneer cells, some binucleate, which are apparently unaffected by the mutation (Doberstein, 1997).

PVR and EGFR signalling during collective migration of border cells

Although directed migration is a feature of both individual cells and cell groups, guided migration has been studied most extensively for single cells in simple environments. Collective guidance of cell groups remains poorly understood, despite its relevance for development and metastasis. Neural crest cells and neuronal precursors migrate as loosely organized streams of individual cells, whereas cells of the fish lateral line, Drosophila tracheal tubes and border-cell clusters migrate as more coherent groups. This study used Drosophila border cells to examine how collective guidance is performed. It is reported that border cells migrate in two phases using distinct mechanisms. Genetic analysis combined with live imaging shows that polarized cell behaviour is critical for the initial phase of migration, whereas dynamic collective behaviour dominates later. PDGF- and VEGF-related receptor and epidermal growth factor receptor act in both phases, but use different effector pathways in each. The myoblast city (Mbc, also known as DOCK180) and engulfment and cell motility (ELMO, also known as Ced-12) pathway is required for the early phase, in which guidance depends on subcellular localization of signalling within a leading cell. During the later phase, mitogen-activated protein kinase and phospholipase Cγ are used redundantly, and it was found that the cluster makes use of the difference in signal levels between cells to guide migration. Thus, information processing at the multicellular level is used to guide collective behaviour of a cell group (Bianco, 2007).

Border cells perform a well-defined, invasive and directional migration during Drosophila oogenesis. They delaminate from the follicular epithelium at the anterior end of an egg chamber and migrate posteriorly, towards the oocyte, as a compact cluster. They then migrate dorsally towards the oocyte nucleus. The border-cell cluster consists of about six outer migratory border cells and two inner polar cells that induce migratory behaviour in the outer cells but seem to be non-migratory. Two receptor tyrosine kinases (RTKs), PDGF- and VEGF-related receptor (PVR) and epidermal growth factor receptor (EGFR), are guidance receptors for border cells. Both receptors act redundantly during posterior migration towards the oocyte, whereas EGFR and its dorsally localized ligand, Gurken, are essential for dorsal migration. Localized signalling from the RTKs is important and actively maintained, especially early in migration. Rac and the atypical Rac exchange factor Mbc (myoblast city, also known as DOCK180) are important effectors. To determine the contribution of Mbc and related proteins, a loss-of-function allele of their common cofactor ELMO (engulfment and cell motility, also known as Ced-12) was generated by homologous recombination. Clusters of elmo mutant border cells arrested early in migration, a defect that could be rescued by expressing elmo complementary DNA. As for mbc, reduction in elmo function suppressed F-actin accumulation caused by constitutive PVR signalling, placing ELMO downstream of the receptor in this respect (Bianco, 2007).

To determine whether later steps in migration also depend on ELMO, mosaic border-cell clusters consisting of wild-type and mutant cells were investigated. If a mutation does not affect migration, mutant cells should be distributed randomly within the cluster. Mutant cells defective in migration would be in the rear, 'carried along' by normal cells. As expected, Pvr and Egfr double mutant cells were in the rear during posterior migration, as were Egfr mutant cells during dorsal migration, reflecting the requirements at each stage. elmo mutant cells were in the rear during the initial migration, but were equally frequent in the leading position during dorsal migration. This indicates that, although ELMO is essential for the early-phase signalling, the later phase of migration does not require the Mbc-ELMO complex (Bianco, 2007).

To understand late guidance signalling, EGFR signalling, on which dorsal migration depends, was dissected. Uniformly activated EGFR, like PVR, dominantly impairs migration. The carboxy-terminal tail of EGFR was essential for this activity. Systematic mutagenesis of all docking tyrosines to phenylalanine identified Y1357 as being critical, with minor contributions from Y1405 and Y1406. Other tyrosines, including Y1095 in the conserved activation loop (phosphorylated in HER2 (Human EGF Receptor 2), were not required. Twenty Src-homology 2- and phosphotyrosine-binding-containing signalling molecules were tested for binding to active EGFR and tyrosine mutants. Y1357 was necessary and sufficient for binding of the adaptor protein Shc and its phosphotyrosine-binding domain. No other tested interactor behaved in this way. Binding was confirmed by immunoprecipitation. Border cells mutant for Shc showed no dorsal migration and, when PVR signalling was also blocked, these cells showed severely impaired posterior migration. This phenotype is identical to that of Egfr mutant cells, suggesting that Shc is essential immediately downstream of EGFR for guidance signalling (Bianco, 2007).

The Shc adaptor protein links EGFR and other RTKs to mitogen-activated protein kinase (MAPK) kinase signalling as well as to other classical downstream pathways. Raf, phospholipase Cγ (PLC-γ) or phosphatidylinositol-3-OH-kinase are not uniquely required for migration; however, the pathways might act redundantly. Simultaneous perturbation of PLC-γ and Raf impaired migration, with no effect of phosphatidylinositol-3-OH kinase. Double mutant border-cell clusters, cell-autonomously lacking PLC-γ and Raf or lacking PLC-γ and MAPK kinase (MAPKK), initiated migration but were delayed later in posterior migration and showed no dorsal migration. This phenotype is more severe than that of Egfr or Shc alone, suggesting that both RTKs might be affected. Prevention of PVR activity in double mutant cells did not block posterior migration, confirming that the requirement for these pathways was stage-specific and not EGFR-specific. Finally, analysis of mosaic clusters showed that Raf/MAPK and PLC-γ were important in late migration, reciprocal to the requirement for elmo. These results genetically define two migratory phases: an early posterior phase requiring ELMO-Mbc and a later posterior and dorsally directed phase requiring Raf/MAPK or PLC-γ. Both RTKs shift effector-pathway-dependency as migration progresses (Bianco, 2007).

To investigate the different migratory phases, border-cell migration was examined via live imaging. Appropriate conditions were establised for culturing and imaging of egg chambers, considering only active, growing ones. Border cells were selectively labelled with green fluorescent protein (GFP) and all membranes were labelled with the vital dye FM4-64. For all 24 wild-type samples, the identity of the front cell changed during the observation period, confirming the inference from fixed samples that cells change position during migration. This indicates that there is no determined front-cell fate. A clear difference was observed in behaviour of clusters during early (first half) and late phases. Early clusters had one, sometimes two, highly polarized cells clearly leading the migration; once these cells delaminated they moved straight and relatively fast. Weakly stained extensions protrude far from delaminating cells and subsequently shorten during movement, suggesting a 'grapple and pull' mechanism. Midway towards the oocyte, strong polarization was lost and cells rounded and started to 'shuffle' while dynamically probing the environment with short extensions. Occasionally the cluster would rotate or 'tumble' completely. This shuffling behaviour still provided effective movement of the cluster towards the oocyte and dorsally, albeit more slowly. Labelling cells with nuclear GFP allowed visualization of changes in positions within the cluster. The front cell exchanged, on average, every 18 min (Bianco, 2007).

As expected, positions corresponding to the second, slower phase of migration were more represented when cluster position along the migratory path was quantified in fixed samples. Also, border cells expressing dominant negative PVR and EGFR were individually active but provided little net cluster movement, as expected from the lack of guidance information. Finally, uniform overexpression of the attractant PVF1 caused an increased shuffling behaviour in the early phase but allowed slow forward movement, resembling normal late migration. This indicates that migrating clusters can interpret a shallow gradient when using the shuffling mode. It also suggests that the normal change in migratory behaviour midway into posterior migration might be triggered by the higher concentration of ligands closer to the oocyte (Bianco, 2007).

The early phase of migration with a highly polarized front cell corresponds temporally to the genetic requirement for ELMO activity. During the later phase, individual elmo mutant cells can alternate with wild-type cells in the lead position. Genetic analysis showed that Raf and MAPKK and, by inference, MAPK activation was sufficient to convey late guidance information. This was puzzling because MAPK activation appeared uniform in migrating border cells, and localized effects are usually a hallmark of guidance signalling. However, signalling that is not localized within an individual cell could still transmit spatial guidance information to the cell cluster if the cell with higher overall signalling indicates the direction of subsequent migration for the whole cluster, as observed for MAPK signalling in border cells. In this 'collective guidance' scenario, each cell of the cluster can be thought of as being analogous to a sector of an individual guided cell. Different levels of signalling in individual cells of the cluster transform into migration vectors because border cells adhere to each other and these contacts differ from substrate contacts. The occasional tumbling of border-cell clusters emphasizes the ability of these cells to behave as a collective unit. Tumbling may help single guided cells to 'reassess' their environment (Bianco, 2007).

To test this model for guidance, the relative levels of signalling in individual cells of the cluster were manipulated. Dynamic shuffling should allow cells to constantly 'compete' for the front position. None of the manipulations discussed below improved migration if all cells in a cluster were affected. Individual border cells with moderately elevated levels of PVR or EGFR were preferentially in the front relative to wild-type cells. Cells with elevated PVR tended to stay in or near the front position, suggesting that they were not competed away by other cells. This bias was ligand-dependent, because reducing PVF1 levels shifted the bias from PVR to EGFR, as was also shown by analysis of dorsal migration. Thus, increased signalling gives a cell-front bias when measuring an informative ligand. Elevating intracellular signalling levels had similar effects, whether by overexpression of an active form of Raf or by preventing downregulation of signalling as in Hrs mutant cells, in which RTK-mediated MAPK signalling is elevated in enlarged endosomes. The more modest front bias in Hrs mutant cells was reflected in behaviour: they could be displaced from the front. The E3 ubiquitin ligase Cbl negatively regulates RTK signalling and is also required to maintain localized RTK signalling within border cells initiating migration. Cbl mutant cells shifted from being preferentially at the back during early stages to being in the front during later migration. This indicates a transition from a mode requiring Cbl-dependent localization of signalling within the leading cell to a mode based on collective decisions within the cluster, in which Cbl mutant cells have an advantage owing to elevated RTK signalling (Bianco, 2007).

It is suggested that guidance of border-cell migration is achieved by two means: signalling localized within the cell, as used in individual migrating cells, and collective guidance, whereby the cluster uses differences in signalling strength among its constituent cells to determine direction. The two modes use the same guidance cues and receptors, but different downstream effectors. Localized signalling is required for the initial, polarized rapid migration, whereas collective behaviour, though observable throughout, dominates in the later phase. Collective decisions on the basis of differences in RTK signalling strength are important in Caenorhabditis elegans vulval development and in branching of Drosophila tracheal tubes, in which they result in specification of discrete cell fates. This differs from the dynamic situation reported in this study, in which the identity of the leading cell constantly changes. Indeed, the frequent exchange of leading cells suggests that front behaviour is normally temporarily restricted, possibly by induced inactivation of signalling. Such dynamics may allow the cluster to better reassess the environment. For guided migration of cell groups, this analysis indicates that sensing and regulation happens both at the single cell level and at the next level-that of collective cell decisions (Bianco, 2007).

Lu, T. Y., Doherty, J. and Freeman, M. R. (2014). DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris. Proc Natl Acad Sci U S A. PubMed ID: 25099352

DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris

Nervous system injury or disease leads to activation of glia, which govern postinjury responses in the nervous system. Axonal injury in Drosophila results in transcriptional upregulation of the glial engulfment receptor Draper; there is extension of glial membranes to the injury site (termed activation), and then axonal debris is internalized and degraded. Loss of the small GTPase Rac1 from glia completely suppresses glial responses to injury, but upstream activators remain poorly defined. Loss of the Rac guanine nucleotide exchange factor (GEF) Crk/myoblast city (Mbc)/dCed-12 has no effect on glial activation, but blocks internalization and degradation of debris. This study shows that the signaling molecules Downstream of receptor kinase (DRK) and Daughter of sevenless (DOS) (mammalian homologs, Grb2 and Gab2, respectively) and the GEF Son of sevenless (SOS) (mammalian homolog, mSOS) are required for efficient activation of glia after axotomy and internalization/degradation of axonal debris. At the earliest steps of glial activation, DRK/DOS/SOS function in a partially redundant manner with Crk/Mbc/dCed-12, with blockade of both complexes strongly suppressing all glial responses, similar to loss of Rac1. This work identifies DRK/DOS/SOS as the upstream Rac GEF complex required for glial responses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris (Lu, 2014).

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myoblast city: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | References

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