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Development of the Cardiac Musculature


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The simplicity of the Drosophila heart paired with the genetic versatility of this model system make it ideal for studying general principles of embryonic patterning and the specification of individual cell types and lineages. Over the past decade, a remarkably comprehensive model of the genetic network involved in the sequential steps of cardiac specification has emerged: (1) the heart field is specified and positioned to dorsal mesodermal margin by the combined action of the ectodermally derived inductive signals encoded by wingless and dpp on the adjacent mesoderm expressing the homeobox transcription factor Tinman. (2) As a consequence, Tinman and the GATA factor Pannier and likely other factors are confined to the cardiac mesoderm, and their combined activity is thought to initiate the formation of the heart. (3) Additional positional information, including patterning by hedgehog emanating from the ectoderm, further subdivides the cardiac mesoderm into distinct segmental units of progenitors, which then undergo stereotyped lineages. (4) Furthermore, the distinction between (anterior) aorta and (posterior) heart proper involves the broad regional specification by the hox genes, most notably abdA. How these genetically identified factors involved in heart formation activate specific enhancers of target genes to generate exquisitely specific patterns of gene expression confined to the heart field are now being elucidated. The insights from Drosophila enabled the discovery of a highly homologous gene network involved in vertebrate heart formation and led to the elucidation of the molecular basis of many forms of congenital heart disease.


The Drosophila heart is a linear tube lying along the dorsal midline of the body axis. It pumps haemolymph through the larval and adult body cavity in an open circulatory system.1,2 Metamorphosis during the pupal stages causes the heart to be substantially remodeled.3-5 The larval heart consists of two major cell types: the inner two rows are contractile muscle cells (myocardial cells), and the outer rows are the pericardial cells that flank them (fig. 1A). Along the anterior-posterior axis of the heart two morphologically distinct sections are distinguishable. The narrower anterior portion is the aorta, while the wider posterior part is the heart proper. These two sections are separated by a simple valve.2 The posterior larval heart also contains three segmental pairs of inlet valves, called the ostia (fig. 1B,C).2,6-8 A row of crescent-shaped myocardial cells from either side of the embryo form a central cavity, the lumen of the heart. Finally the heart is suspended along to dorsal midline epidermis by means of small somatic muscles.

Figure 1. A) Photomicrograph showing the cardiac musculature.

Figure 1

A) Photomicrograph showing the cardiac musculature. The myocardial nuclei are positive for Dmef2 (blue) and the pericardial cells are positive for Pericardin (brown). Note blue myo-cardial nuclei in between brown percardial cells. B) Myocardium of the (more...)

From Mesoderm to Heart Progenitors

During gastrulation, in the ventral third portion of the Drosophila blastoderm embryo, the presumptive mesoderm invaginates in a furrow along the ventral midline and localizes internally (fig.1D). Once internalized the mesoderm flattens and spreads dorsally by cell migration, forming a morphologically uniform monolayer of cells in close contact with the ectoderm. 9 Coincidentally, the long germband folds over and extends anteriorly to bring the posterior end of the embryo in proximity with the head region (fig. 2). After the mesodermal monolayer reaches the dorsal edge of the ectoderm, molecular markers begin to distinguish the dorsal from the ventral portion of the mesoderm, followed by the first discernable morphological subdivisions (fig. 1D). The dorsal mesoderm gives rise to the outer dorsal somatic mesoderm and the inner visceral mesoderm. The dorsal mesoderm forms mostly somatic muscles. The inner visceral mesoderm segregates as an epithelium, and serves to guide the migration of the mid-gut primordia that grow in from the embryo's anterior and posterior ends.10-12 In close temporal sequence the heart progenitors emerge at the dorsal-most edge of the outer layer of the dorsal mesoderm. They form the cardiac mesoderm (fig. 2).13,14 The fat body and somatic gonad are also specified at this time.15,16

Figure 2. Stages of cardiac mesoderm and heart tube assembly.

Figure 2

Stages of cardiac mesoderm and heart tube assembly. A) Side view of heart field at late stage 11 germ band extension. B) Side view of heart progenitors at stage 13 germ band retraction. C) Dorsal view of bilateral rows of cells in the process of migration (more...)

The bilaterally symmetrical heart primordia form at the germ band extended stage (fig. 2). Then following germ band retraction (fig. 2) the two rows of cardiac mesoderm move towards the dorsal midline (fig. 2). Here they assemble into a linear tube (fig. 2). As the myocardial cells align in register with one another they assume an apical-basal (dorsal-ventral) polarity.17,18 While the molecular-genetic basis of cardiac morphogenesis has not yet been studied in detail, many of the molecular determinants of cardiogenesis have been identified. Their homologues in vertebrates have functions that are remarkably conserved.14,19-23

Cardiac Lineages

The lineages that contribute to the cell types forming the heart tube and surrounding pericardial cells have been studied in considerable detail (Figs. 4.1D, E).24-28 Within the emerging cardiac anlagen (primordial cells) at the dorsal mesoderm edge (fig. 2) groups of progenitors express distinct combinations of transcription factors (fig. 1D), and undergo stereotyped patterns of cell division to generate cardiac cell diversity (fig. 1E).

The cardiac progenitors emerge as a two to three cell-wide unit of dorsal mesodermal cells at mid-stage 11, when most if not all express the Tinman (Tin) homeobox transcription factor (fig. 1B,C). They extend from the third thoracic segment (T3) to the eighth abdominal segment (A8).13,29 Additional markers are then expressed in subsets of prospective heart cells (fig. 1B,C). The even-skipped (eve) segmentation homeobox gene is expressed in two pericardial cells with large nuclei in each hemisegment.30 The tandem homeobox genes ladybird (lbe)31 is also expressed in two pericardial cells. The Seven-up COUP steroid receptor (Svp)32 is expressed in two myocardial cells and also two pericardial cells. The two myocardial cells coexpress the dorsalcross T-box encoding genes,33 whereas two of the four pericardial cells coexpress the zinc finger protein Odd-skipped (Odd) and the remaining two are Svp-positive.34 Tin is expressed in two myocardial cells and at least four pericardial cells. Two of the pericardial cells coexpress eve and the other two coexpress lbe.27,35 The myocardial cells share characteristics with other muscle forming mesodermal cells such as expression of Dmef2, a MADS-box transcription factor (fig. 1A),36-39 muscle myosin heavy chain40 and beta-3-tubulin.41

Interestingly, some of the heart precursors divide symmetrically, whereas others exhibit asymmetric cell division patterns. Two sets of asymmetric lineages have been described in the cardiac mesoderm based on cell division patterns24 clonal analysis.27,34 and cell cycle mutant phenotypes.28 The Svp lineage generates two myocardial cells and two pericardial cells per hemisegment, whereas the Eve lineage generates two Eve pericardial cells and two founder cells for dorsal somatic muscles. Thus, cardiac and somatic muscle associated cells do not always derive from separate lineages. A common feature of the cardiac asymmetric lineages is that they distinguish between myogenic and nonmyogenic sibling cell fates. In the case of the Eve lineage, one Eve progenitors per hemisegment generates two Eve pericardial cells and a somatic muscle founder cell (DO2/8 ie muscle letter/number hereon). In contrast the other Eve progenitor in the hemisegment gives rise to another muscle founder cell (DA1/1) and an unidentified sibling. The final division of the immediate precursor of the Eve pericardial cells is then symmetrical. The other heart associated cell fates in the main portion of the heart (A2-8) undergo symmetric cell divisions, which is in contrast to the ‘outflow track’ (T3-A1), where most lineages appear to be asymmetric.27,28

Studies of cell cycle mutants suggested some interesting features of these cardiac lineages.28 Most cells in the developing embryo undergo only three additional, partially synchronous rounds of cell division after the blastoderm stage, with the notable exception of the CNS.42,43 The last round of global cell division, mitosis 16, is blocked in cyclinA (cycA) mutants.44,45 CyclinB (cycB) mutants have no obvious effect during these divisions, but cycA,cycB double mutants synergistically arrest at cycle 15.44 In embryos mutant for string (stg) (cdc25 in yeast), cell division is already arrested at cycle 14.42,46,47 The CDK inhibitors Dacapo and Fizzy-related negatively regulate Cyclin levels and are required to exit the cell cycle.48,49 Heart precursors continue to differentiate in cell cycle mutants and in embryos in which cell cycle inhibitors are overexpressed. The cell fate of symmetrically dividing progenitors of either myocardial- or pericardial-only lineages is not altered by premature arrest of cell division. In contrast, arrested progenitors of the asymmetric Eve and Svp lineages always adopt a myogenic, as opposed to pericardial fate (fig. 1E, middle panel). In cycle 15 arrested cycA;cycB double mutants, only two of the normally six myocardial cells are formed. One expresses tin and the other svp. This suggests that in each hemisegment two higher order myocardial progenitors are initially specified, one giving rise to the tin-expressing myocardial cells and the other to the svp-positive myocardial and pericardial cells. In conclusion, there are probably 5-6 cardiac progenitors specified in each hemisegments.

The molecular basis for specifying alternative cell fates during asymmetric cell division has been elucidated in some detail, and involves asymmetric segregation of intracellular determinants between the progenitor and its daughter cells. The presence of the membrane-associated numb gene product is necessary and sufficient for specifying a daughter cell fate that is different from its Numb devoid sibling. This occurs by inhibiting the activation of the transmembrane Notch receptor and a four-pass transmembrane protein encoded by sanpodo.26,50-59 In the Drosophila heart, the asymmetric eve and svp lineages are under the control of numb, Notch and sanpodo.25,27,28,34,60

In contrast to the asymmetric lineages, constitutive activation or repression of the Notch pathway has no apparent effect on the symmetric myocardial-only or pericardial-only lineages. Following numb loss-of-function or ectopic Notch activation there are twice the number of svp and eve pericardial cells at the expense of the svp myocardial or eve muscle founder cells. In contrast the number of tin-expressing myocardial cells and the other pericardial cells are unaffected. When numb is overexpressed the opposite phenotype is observed in svp and eve lineages, but again without affecting cell fate of the symmetrical lineages. Hence regulation of Notch signaling dramatically affects cell fate in asymmetric lineages by preventing a myogenic fate, but even forced expression is incapable of altering the myogenic- or pericardial-only fate of symmetrically dividing progenitors. These conclusions are also supported by experiments in which cell cycle mutants are combined with lineage mutants (fig. 1E, lower panel).28 Remarkably, a switch from Notch insensitivity to Notch responsiveness can occur even within the same lineage: the initial svp progenitor first divides symmetrically then asymmetrically, whereas the Eve pericardial cells progenitor first divides asymmetrically and then symmetrically. It may very well be that a convenient way to increase complexity of an organism during evolution is through regulating numb/Notch responsiveness during phases of cell proliferation.

Specification and Positioning of the Cardiac Mesoderm

The mesoderm, which is a prerequisite of heart formation, depends on formation of the embryonic dorsal-ventral body axis.61 The first mesoderm-specific genes that are activated in the ventral third of the blastoderm embryo are twi and snail, encoding a basic helix-loop-helix and a zinc finger protein respectively.62,63 Twi acts as a positive determinant of mesoderm, whereas Snail acts by repressing neuroectodermal gene expression within the mesodermal anlagen.64-69 At the blastoderm stage Twi turns on: Tin;13 Zinc Finger Homeodomain Protein-1, a nuclear protein containing a homeodomain and several zinc fingers;70,71 Heartless (a.k.a. DFR1), a membrane protein of the Fibroblast Growth Factor receptor family,72-75 Drac1, a GTPase;76 Pointed P2, an ETS transcription factor;77 and Dmef2, the Drosophila member of the Myocyte Enhancer Factor-2 family of MADS-box-containing nuclear proteins.36-39 Twi and its targets are likely to provide a mesoderm-specific context for appropriate differentiation of mesodermal derivatives.

During gastrulation the mesodermal anlagen invaginates along the ventral midline. The mesoderm then flattens into a monolayer that spreads dorsally in close apposition to the ectoderm, a process requiring Heartless function.73-75 If the mesoderm does not come into contact with the dorsal ectoderm, heart and visceral muscle formation is severely reduced. As outlined below, secreted signals emanating from the dorsal ectoderm are crucial for inducing cardiogenesis (reviewed in ref. 78). In contrast to Heartless' role in cell migration, Tin is crucial for mesodermal regionalization and specification of dorsal fates.

Although tin is first expressed uniformly in the presumptive trunk mesoderm, directly dependent on Twi,13,79 it is restricted to the dorsal portion of the mesoderm at stage 10. tin mutants primarily lack derivatives of the dorsal mesoderm, including the heart, the visceral and a set of dorsal somatic body wall muscles.12,35 Thus, specification of ‘dorsal mesoderm’ by Tin is crucial for subsequent subdivisions and differentiation. Dorsal mesoderm specification, including tin expression, also depends on the product of decapentaplegic (dpp). dpp encodes a secreted factor that is a member of the Transforming Growth Factor-β (TGF-β, superfamily, and is required for formation of the dorsal-ventral axis.61,80-82 dpp is expressed in the dorsal ectoderm and signals across germlayers to pattern the underlying dorsal mesoderm (reviewed in ref. 78).83-85 From mid-stage 11 on tin is further restricted to the heart progenitors in the trunk region (fig. 2A), and is maintained through adulthood.5 Enhancer elements of tin have been found that direct expression in the early mesoderm, the dorsal mesoderm and cardiac mesoderm.79,85,86

Although dpp is required for heart formation and cardiogenesis, the restriction of tin expression to the heart-forming region at the dorsal mesodermal margin requires additional positional information. This pattering information is provided by the striped expression of the segmentation gene wingless. This gene encodes a secreted glycoprotein of the Wnt class, and is essential for cardiac specification.87,88 Genetic evidence suggests that the dynamic expression patterns of dpp, wingless and tin is not only essential but also instructive for initiating cardiogenesis and correct positioning of the heart progenitors.89 Recently it was shown that the cardiac restricted expression of pannier, which encodes a GATA transcription factor, with tin provides heart-forming competence within the mesoderm.90-93

In Drosophila, wingless is expressed and required in two phases of heart development.31,87,89 The first phase is mediated by the canonical wingless pathway.88 This contrasts with vertebrates, where it appears to be noncanonical Wnt signaling that promotes cardiogenesis.94 It remains to be determined whether in flies the second phase of cardiogenic wingless signaling is noncanonical. dpp also has two phases of expression: first in broad dorsal ectodermal band, and later in a narrow stripe along the dorsal ectodermal margin above the cardiac progenitors. It is tempting to speculate that dpp, like wingless, also acts in two phases to initiate heart development. pannier is a target of dpp in the ectoderm and is, in turn, required for maintaining the late phase of dpp expression.93,95,96 This led to the model where the convergence of wingless and dpp signaling initiates and maintains tin and pannier expression in the cardiac mesoderm, then these transcription factors provide the appropriate cardiogenic context for heart development to proceed.21,89,93 Therefore the genetic cascade of heart specification is: Pannier Twist → Tinman (meso); Wingless, Dpp (ecto) → ↓ ↑ → cardiogenic fate Tinman pannier is a likely direct target of Tin.97 Yet pannier overexpression throughout the mesoderm results in transient, ectopic tin expression. This suggests that both of these transcription factors are required to maintain each other's expression. tin and pannier may in fact act synergistically in specifying cardiac development, since mesodermal overexpression of both but not either alone induces robust and sustained expression of cardiac-specific markers, such as the basic Helix-Loop-Helix transcription factor encoded by dHand and the ABC-class transmembrane protein encoded by dSUR.93 This is consistent with in vitro experiments using vertebrate cell lines, in which it was shown that the vertebrate homologs of these genes activate target genes synergistically (e.g., refs. 98-100). Taken together, the following sequence of events is a probable scenario of cardiogenesis: at stage 9/10 dpp maintains tin expression in the dorsal mesoderm and pannier expression in the dorsal ectoderm. At early to mid-stage 11, tin and dpp/wingless initiate pannier in the cardiogenic region, and pannier and dpp/wingless maintain tin expression in the heart field. Later, tin and pannier maintain each other, and ectodermal pannier maintains late dpp expression.

A set of T-box genes, encoded by neuromancer I (a.k.a. H15)101 and its neighbor neuromancer II, may also participate in determining cardiogenesis.101a Interestingly, in vitro protein binding and transactivation studies in vertebrates suggest a synergistic relationship between Nkx, Gata and T-box transcription factors.102,103 In the future, it will be interesting to see if the combination of tin, pannier and neuromancer genes is not only essential but also sufficient in promoting heart formation.

Specification of Cardiac Cell Types

The next question of interest is how individual cell fates are specified within the heart field, a process which may occur in parallel with the overall cardiac initiation. Four groups of heart progenitors emerge within the prospective cardiogenic region in stereotyped, segmentally repeated clusters, expressing either eve, lbe, svp or odd.30,31,58,60,104 The first clusters to emerge within a segmental unit are the eve cells, at a time when tin is still expressed in the entire dorsal mesoderm. The specification of the cell types expressing mesodermal eve and the regulation of this expression has been extensively studied.25,24,71,104-108 In addition to dpp, wingless, tin and twi, specification of the eve clusters also requires ras-mediated input from Epidermal Growth Factor and Fibroblast Growth Factor receptor tyrosine kinases. Eve is not only a marker for the cells it is expressed in but is also required as an identity gene for their correct differentiation. 60,71,104 To study eve's role in the mesoderm, the enhancer responsible for mesodermal eve expression was selectively eliminated in a genomic rescue construct.109 Flies that are null mutant for eve but contain this ‘eve meso minus’ rescue construct as a transgene are viable but lack the mesodermal eve clusters and exhibit defective heart function.

Anterior to the eve clusters in each segment emerge the lbe clusters.31 In lbe loss-of-function mutant the eve clusters are enlarged, while mesodermal overexpression of lbe suppresses eve.60,104 Conversely, ‘eve meso minus’ rescue embryos have expanded lbe expression, and mesodermal overexpression of eve eliminates lbe expression in the heart. This suggests that eve and lbe repress each other and are thus present in nonoverlapping clusters.

lbe is also required in a group of ectodermal cells that contact the outflow track of the heart.110 This is reminiscent of the neural crest cells that pattern the cardiac outflow track in vertebrates.111 Posterior to the Eve cells are the svp-expressing cell clusters near the segmental boundaries (see also fig. 1B,C). svp is first coexpressed with tinman, but then suppresses it in the svp cells.5,6,7 Unlike lbe and eve, however, svp gain- or loss-of-function does not influence cardiac eve or lbe expression. The fourth group consists of two sets of odd-expressing pericardial cells,34 one of which also expresses svp. The function of odd in the heart has not yet been determined.

How the genetic information leading to precise positioning of cardiac cell types is integrated at the transcriptional level has been studied in detail using eve's mesodermal enhancer (eme).104,107,109,112 eme contains multiple consensus or in vitro binding sites for all the transcription factors that are required genetically for eve expression in the cardiac mesoderm, such as for Pangolin/dTCF (wingless pathway), Mad (dpp pathway), Pointed (ETS factor, ras pathway), Twi and Tin.104,107,112 Overall, these sites seem to act in an additive fashion, such that mutating progressively more tin sites eventually eliminates reporter gene expression. Therefore the genetic network that provides cardiogenic competence to the dorsal edge of the mesoderm also acts combinatorially at a single enhancer.

The above activator inputs appear to explain well why mesodermal eve is expressed within the cardiac mesoderm, but they do not explain how eve transcription is confined to a rather small segmental cluster within the heart. Since Lbe acts genetically as a repressor of eve, it may do so by direct interaction with the mesodermal eve enhancer. Indeed, Lbe not only binds to the enhancer in vitro, but mutating the corresponding sites leads to an expansion of reporter gene expression to encompass the entire heart field in vivo.104 In addition, eme without Lbe consensus sites is no longer repressible by Lbe as expected when Lbe directly regulates eve in the mesoderm. In summary, the precision of mesodermal eve expression is achieved by a combination of activators and repressors converging on a small enhancer.

Formation of the neighboring eve and lbe clusters in each segment requires a similar combination of activating genetic inputs (dpp, wingless, tin, etc.) and they exclude each other from their territory by mutual repression. It is unclear, however, what mechanism positions the eve progenitors posterior to lbe. An emerging candidate is hedgehog, which is expressed in stripes adjacent and posterior to those of wingless, and is already known to be required for heart formation via its role in maintaining wingless expression.87,88 To test for additional cardiac patterning functions, hedgehog has been eliminated while maintaining wingless. Interestingly, in such hedgehog off—wingless on embryos the eve cell clusters do not form and the lbe clusters are expanded to all tin-expression cardiac progenitors (J. Liu, L. Qian and R. Bodmer, unpublished data). Overexpression of hedgehog and activation of the ras pathway expands eve and reduces lbe in the cardiogenic mesoderm106 (J. Liu, L. Qian and R. Bodmer, unpublished data). Moreover, manipulation of hedgehog alters the cardiac levels of rhomboid mRNA, which codes for a protease that regulates Epidermal Growth Factor receptor-mediated ras activation. These findings suggest that hedgehog, via augmenting ras signaling, activates the mesodermal eve cells nearby in the underlying mesoderm, and inhibits the lbe clusters. These then form further away. The mutual repression between eve and lbe then maintains the stereotyped anterior-posterior arrangement of these cell fates within each segment. In conclusion, we now understand some of the basic genetic principles by which individual heart progenitors and their progeny are specified, positioned and distinguished from their neighbors.

Many more genes are likely involved in cardiogenesis, either during specification or at a later differentiation step. Two gene functions have recently been identified that when mutated cause a dramatic increase in the myocardial cell population of the heart: the ETS gene pointed and the muscle-specific homeobox (msh) gene.27,60 msh and pointed may restrict the number of heart progenitors to the most dorsal region of the mesoderm as well as play a role in specifying dorsal skeletal muscle founders. msh seems to act in a cross-repressive network with lbe and eve to specify spatially restricted cardiac (and skeletal) cell fates; and in the case of pointed, it has been suggested that its role in determining myocardial cell number is likely in addition to its function as an effecter of the ras pathway. In order to find additional gene functions that participate in cardiogenesis, heart-specific gain- and loss-of-function screens have recently been carried out. In a gain-of-function screen based on mesoderm-specific overexpression 84 out of 2,293 gene functions were found to affect lbe or eve expression.108 In a RNAi-based loss-of-function screen 132 out of 5,849 genes altered embryonic heart morphology.113

Hox Gene Function in the Heart

In addition to the segmental specification described earlier, the embryonic heart is divided into three regions (fig.2): the outflow track (T3-A1), the aorta (A2-A5) and the wider posterior heart (A6-A8), which also contains six wingless-expressing haemolymph inlet valves known as ostia (fig.1 and fig. 2).5 Three studies have recently elucidated the role of the hox genes in this broad regionalization of the heart (reviewed in ref. 29).8,114,115

The principle hox gene player involved in discriminating between the aorta and the posterior heart is abdominal-A (abd-A). The expression pattern of other hox genes in the embryonic heart is arranged in an anterior-posterior pattern (fig.1B,C), reminiscent of their nested expression pattern during segmental identity specification in the early embryo. Antennapedia (Antp) is expressed primarily in the outflow track A1 region, Utrabithorax (Ubx) at high levels in the aorta (A2-A5), abdominal-A (abd-A) is confined to the posterior heart (A6-A8), and Abdominal-B (Abd-B) is expressed in the four posterior-most myocardial cells.

abd-A acts as the homeotic selector for posterior heart identity. In abd-A mutants expression of troponinC-akin1 (tina1) and wingless in the posterior heart is abolished. In addition the posterior heart looks like the aorta and expresses Ubx at high levels. Conversely, in embryos in which abd-A is expressed uniformly in the mesoderm or exclusively in the heart the anterior portion of the heart is now wider in diameter expressing tina1 and forming wingless expressing ostia throughout.

Since Ubx is prevalent more anteriorly than abdA (fig. 2), it may be the homeotic selector gene for a ‘posterior aorta’ fate. As expected, loss-of-Ubx-function does not alter posterior heart differentiation. The Ubx mutant aorta exhibits only minor abnormalities in epithelial polarity,8 and there is no alteration of tina1 or svp expression. In Ubx, abd-A double mutants no significant additional changes are observed in the myocardium, although not enough outflow track markers are available to assess a possible anterior transformation. In contrast, the pericardial lymph gland primordia in A1 are expanded along the entire aorta in Ubx mutants,116 consistent with a mesoderm-autonomous homeotic function of Ubx. However, when Ubx is overexpressed uniformly in the mesoderm abd-A expression in the heart is not altered, but surprisingly tina1 is expanded anteriorly as with abd-A overexpression. This suggests that in this overexpression assay Ubx can partially substitute for its relative abd-A. In contrast the pan-mesodermal overexpression of abd-A's posterior relative Abd-B (fig. 1B,C) completely suppresses cardiogenesis, and in Abd-B mutants additional myocardial cells are formed more posteriorly.113 Taken together, these findings suggest that the hox genes function autonomously within the heart progenitors to specify correct regional identities along the anterior-posterior axis.


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