The medaka fish (Oryzias latipes) is an emerging model organism for which a variety of unique developmental mutants have now been generated. Our recent mutagenesis screening of the medaka identified headfish (hdf), a null mutant for fgf receptor 1 (fgfr1), which fails to develop structures in the trunk and tail. Despite its crucial role in early development, the functions of Fgfr1-mediated signaling have not yet been well characterized due to the complexity of the underlying ligand-receptor interactions. In our present study, we further elucidate the roles of this pathway in the medaka using the hdf (fgfr1) mutant. Because Fgfr1 is maternally supplied in fish, we first generated maternal-zygotic (MZ) mutants by transplanting homozygous hdf germ cells into sterile interspecific hybrids. Interestingly, the host hybrid fish recovered their fertility and produced donor-derived mutant progeny. The resulting MZ mutants also exhibited severe defects in their anterior head structures that are never observed in the corresponding zygotic mutants. A series of detailed analyses subsequently revealed that Fgfr1 is required for the anterior migration of the axial mesoderm, particularly the prechordal plate, in a cell-autonomous manner, but is not required for convergence movement of the lateral mesoderm. Furthermore, fgfr1 was found to be dispensable for initial mesoderm induction. The MZ hdf medaka mutant was thus found to be a valuable model system to analyze the precise role of fgfr1-mediated signaling in vertebrate early development.
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In this study, we demonstrate that the Gata4 lateral mesoderm enhancer requires an essential Forkhead-binding site that is efficiently bound by FOXF1 (Figs 6, 8), supporting the possibility that BMP activation of Gata4 could be mediated by FOXF1 or other Forkhead proteins. Indeed, a recent study performed in Xenopus embryos has shown that Foxf1 expression is reduced when BMP4 signaling is reduced, indicating that FOXF1 is also a downstream target of BMP4 (Tseng et al., 2004). Interestingly, however, Bmp4 has been shown to be a potential target of FOXF1 during mouse development, as the level of Bmp4 mRNA was significantly reduced in the posterior primitive streak, the lateral plate and the allantois in FOXF1 null embryos (Mahlapuu et al., 2001b). Taken together, these results suggest that FOXF1 and BMP4 may function in a reinforcing regulatory circuit designed to amplify a transcriptional response downstream of BMP4 signaling, possibly via GATA and other transcription factor families. GATA transcription factors also appear to activate Bmp4 expression, further supporting the notion of a reinforcing transcriptional network (Nemer and Nemer, 2003; Peterkin et al., 2003). The mouse and Xenopus Bmp4 regulatory sequences contain GATA-binding sites that are functional in studies performed in vitro, suggesting that Bmp4 expression may be activated or maintained by GATA factors (Nemer and Nemer, 2003; Peterkin et al., 2003). A reinforcing transcriptional model is consistent with the work presented here, which suggests a model for Gata4 activation in the lateral mesoderm in which BMP4 activates the expression of Gata4 indirectly via FOXF1, and GATA4 functions in a positive-feedback loop to reinforce its own expression through essential GATA sites in its enhancer (Fig. 10).
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In order to probe functions for the pathway in the specified progenitors for these specific lineages, it was necessary to generate a conditional approach to block BMP signaling during somitogenesis within lateral mesoderm. Our results demonstrate that BMP signaling functions in lateral mesoderm to affect the decision of progenitors to commit either to a hemato-vascular fate, or to a pronephric fate. Transgenesis facilitated by the I-SceI meganuclease provides an effective approach that is limited only by the availability of appropriate promoters. The lmo2 promoter was ideal for our purpose as it is not expressed until around the one-somite stage, and therefore genes expressed using this promoter will not interfere with development prior to this point. However, the lmo2 gene is subsequently activated throughout lateral mesoderm and so can be used to regulate simultaneously gene expression in the progenitors for hematopoietic, vascular and pronephric lineages. Our results indicate that BMP signaling does continue to regulate development of lateral mesoderm within Lmo2+ cells and acts at this stage to restrict hemato-vascular development and promote pronephric mesoderm. Although the increased numbers of hematopoietic cells could be caused by changes in cell proliferation, immunohistochemistry using anti-phospho-histone H3 antibodies failed to show any significant increase in mitotic cell numbers in embryos expressing the mutant BMP receptor (data not shown). Instead, the data support a model in which decreased levels of BMP signaling within lateral mesoderm results in changes of lineage fate, with increased numbers of hemato-vascular progenitors occurring at the expense of pronephric progenitors. This interpretation relies on the assumption that BMP ligands are normally expressed and active at these later stages of development. Although the expression patterns for a number of potential ligands are not fully described, there are clear candidates for the functional signal, including Bmp2b [in ventral mesoderm (Kishimoto et al., 1997)], Bmp4 [in posterior epidermis, tailbud and lateral mesoderm (Dick et al., 1999)] and, perhaps most strikingly, Bmp6, which is expressed in the two stripes of ventral mesendoderm during early stages leading into somitogenesis (Thisse and Thisse, 2005).
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Fig. 4. Ipl transcript accumulation between 5.5 and 9.5dpc of mouse development. (A) Lateral view of 5.5 dpc embryo shows Ipl transcripts localised to the ectoplacental cone (white arrow head) and the extra-embryonic ectoderm (white arrow). A line indicates the embryonic (E) and extra- embryonic (eE) boundary. (B) Lateral view of an early primitive streak stage embryo (posterior to right). Ipl transcripts localised to the ectoplacental cone and the first mesoderm to arise from the primitive streak (arrow). (C) Full length primitive streak stage embryo (posterior to right). Ipl tran- scripts are localised to nascent extra-embryonic mesoderm and proximoposterior nascent embry- onic mesoderm. A line indicates the embryonic (E) and extra-embryonic (eE) boundary. (D) Lateral view of head fold stage embryo (posterior to right). Ipl transcripts were localised to all extra-embryonic tissues; ectoplacental cone, chorion (white arrow), yolk sac (white arrow head), allantois (black arrow) and amnion plus presumptive lateral mesoderm (lm). (E) Transverse section of embryo in (A); level of section indicated by solid black line. Ipl tran- scripts were localised to the extra-embryonic ecto- derm but not the visceral endoderm. (F) Transverse section (posterior to right) in the extra-embryonic region of embryo in (C); the level of the section indicated by solid black line. Ipl transcripts were localised to the nascent extra-embryonic meso- derm (white arrow) just detected in the extra- embryonic ectoderm (black arrow) but not detected in the extra-embryonic visceral endoderm (black arrow head). (G) Transverse section (posterior to right) in the embryonic region of embryo in (C); level of section indicated by solid black line. Ipl tran- scripts were localised to the nascent embryonic mesoderm (white arrow), but not to the ectoderm (black arrow) or endoderm (black arrow head). (H) Posterior view of a head fold stage embryo, similar stage to the embryo in (D). Ipl transcripts were
Recent analyses of the interface between paraxial and lateral mesoderm populations at limb levels (Nowicki et al., 2003) offer an alternative model that applies well to the head. We propose that the neural crest:mesoderm interface is in fact not crossed by aggregated muscle primordia or by crest-derived connective tissues. Instead, the interface is a deformable plane. Localized sites of differential growth or changes in adhesive properties within populations on either side of the interface cause the formation of finger-like projections that appear to penetrate the interface but in fact only deform it. This model closely resembles ‘convergent extension’ (Wallingford et al., 2002), the process by which cell reorganization within embryonic epithelial sheets occurs. Structures such as the DO do not move across the interface, but rather are embedded within tips of expanding mesodermal projections. Later, crest cells encircle these mesodermal projections, isolating extra- ocular or branchial muscles from the more proximal parts of the mesodermal projections.
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The first step in the establishment of the Fgf feedback loop is the activation of Wnt3a and Fgf8 in the AER, in response to Fgf10 from the lateral mesoderm (Kawakami et al., 2001; Kengaku et al., 1998; Ohuchi et al., 1997). This is followed by reciprocal Fgf8 signalling to the mesoderm, which stabilizes Fgf10 expression. To investigate if the neck ectoderm is able to respond to Fgf10 and then signals back to the lateral mesoderm, beads soaked in Fgf10 protein were grafted into the neck lateral mesoderm at the right side of HH11-14 chick embryos at different positions along the anteroposterior axis (see Table S3 in the supplementary material). As a positive control, Fgf10 beads were placed into the flank of HH13-15 embryos, as Fgf10 has been shown to trigger the development of an ectopic limb (Yonei-Tamura et al., 1999). Indeed, Fgf10 beads induced an ectopic bud in the flank, the AER of which expressed both Wnt3a (n=2/2, Fig. 5D) and Fgf8 (n=2/2, Fig. 5G), and consequently, the mesoderm of which expressed Fgf10 (n=2/2, Fig. 5A). Thus, the beads released a sufficient amount of Fgf10 protein to establish the Fgf10-Fgf8 regulatory loop and to induce the development of a limb in the flank. By contrast, in the neck neither Wnt3a (n=17/17, Fig. 5E) nor Fgf8 (n=6/6, Fig. 5H) were expressed above the Fgf10 beads and, as a result, Fgf10 was not expressed in the neighbouring neck mesenchyme (n=11/11, Fig. 5B).
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Xenopus FoxF1 is first activated during gastrulation in the presumptive ventro-lateral mesoderm. During neurulation, FoxF1 expression becomes restricted to the lateral plate mesoderm (El-Hodiri et al., 2001; Koster et al., 1999). This expression is very similar to the expression of its murine ortholog HFH-8 (Foxf1) (Peterson et al., 1997) with some species-specific differences. While both of the genes are expressed in the lateral plate mesoderm and later in the visceral mesoderm, the murine Foxf1 is intensely transcribed in the extra-embryonic mesoderm of allantois, amnion and yolk sack, structures that do not exist in Xenopus embryos. Interestingly, even the Drosophila gene biniou displays a highly conserved expression in the visceral mesoderm. The unique expression pattern of FoxF genes in the lateral plate/visceral mesoderm makes them important targets for evaluation of function in order to shed light on their role in gut development. In vertebrates, the function of Foxf1 has been investigated only in mice. A targeted elimination of Foxf1 resulted in defects in mesodermal differentiation and incomplete separation of splanchnic and somatic mesoderm (Mahlapuu et al., 2001b). Analysis of Foxf1 function in older mouse embryos was hampered by the fact that the Foxf1 deficient embryos have severe defects in extra-embryonic structures, and these animals die of apoxia by embryonic day (E) 10.
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from the ventral and lateral mesoderm, which might not require dorsolateral migration to receive patterning signals from the ectoderm. In late embryos, we observed a range of somatic muscle defects consistent with the participation of FGF signalling in specific cell fate decisions (Fig. 6). Wild-type embryos develop a stereotyped arrangement of ~30 body wall muscles in each hemisegment, with variations in the anterior and posterior regions of the embryo (Bate, 1990). Each muscle arises from a single founder myoblast, specified at a defined segmental position through the influence of ectodermal signals on the expression of mesodermal factors (Baylies et al., 1998). It was noted previously that expression of dominant-negative Htl blocks formation of ventral oblique (VO) muscles and that an intact ventral nerve chord is required for their formation (Beiman et al., 1996; Michelson et al., 1998; Schulz and Gajewski, 1999). This implied that FGF ligands expressed in the ventral neuroblasts might be required for founder specification for these muscles. Pyr and Ths are both expressed in a subset of neuroblasts (see Fig. S4 in the supplementary material) and we found that ventral oblique muscles VO4, VO5 and VO6 are affected in pyr 18 and ths 759 homozygous mutants (Fig. 6A-G). Defects in pyr 18 were more frequent when the
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Fig. 5G, Mo-1 clearly induces the expression of mesodermal markers in a dose-dependent manner although the induction level was weaker than that induced by XSmad2 overexpression, while expression of XSmad1 and β-catenin targets were not affected. Finally, to confirm whether the effects of Mo-1 are specific, we designed a second morpholino (Mo-2) and a mutated Mo-1 (Mo-mut) that has five point mutations (Fig. 5A) and analyzed their function. Effects of Mo- 2 on induction of mesoderm markers (Fig. 5F, part d; 5H) and animal cap elongation (data not shown) were almost identical to those by Mo-1, while Mo-mut did not show any effect on our analysis, including mesoderm marker induction (Fig. 5H, data not shown). Moreover, the induction of mesoderm markers by Mo-2 was completely suppressed by co- introduction of XPIASy mRNA, which does not have 5′- noncoding region (Fig. 5I). These observations demonstrate that endogenous XPIASy functions as a negative regulator of XSmad2 and that the XSmad1 and Wnt pathways are not main physiological targets of XPIASy. Furthermore, taken together with the XPIASy expression pattern and gain-of-function analysis, all observations clearly indicate that XPIASy functions as a gatekeeper in early embryonic patterning to avoid unscheduled activation of XSmad2 in inappropriate places.
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Successful patterning of the embryo, from establishing the three primary axes to the regional specification of tissue progenitors is essential to generating a viable embryo. The three germ layers in the early embryo undergo patterning through slightly different mechanisms. The tissue of interest to this study is the lateral plate mesoderm (LPM), which will give rise to the lineages of the cardiovascular system and is essential for regional specification of adjacent germ layers. However, little is known about how the LPM itself undergoes regional specification and attains its intitial patterning after gastrulation. Here, I will demonstrate that a complex pattern of gene expression exists across the entire LPM shortly after gastrulation, much earlier than previously recognized. Furthermore, I will use molecular techniques to elucidate the signalling factors involved in the early patterning and regional specification the LPM. I hypothesize that both the retinoic acid (RA) and Fibroblast Growth Factor (FGF) signalling pathways are involved in the LPM regional specification in the neurula stage embryo. Through the use of exogenous modulators of the RA pathway, I will show that RA signalling is essential for patterning the anterior-dorsal and middle LPM domains. Secondly, by addition of a synthetic FGF receptor inhibitor I will demonstrate that FGF signalling is essential for establishing the anterior-ventral and posterior domains of the LPM and functions
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raises the possibility that nkx2.5 and ltbp3 reside in a common genetic pathway. Most likely, nkx2.5 functions upstream of ltbp3 based on the observation that SHF progenitors express nkx2.5 in the ALPM prior to initiating expression of ltbp3 in pharyngeal mesoderm [this study and (Zhou et al., 2011)]. To test this hypothesis, we performed in situ hybridization for ltbp3 transcripts in nkx2.5 morphants. At the 23-somite stage (20.5 hpf), when ltbp3 expression initiates in the cardiac cone, no obvious difference in ltpb3 expression was observed between control and morphant embryos. (Fig. 6A,B), suggesting that SHF progenitors were specified properly in nkx2.5 morphants. However, after the linear heart tube is established (28 hpf), we observed a qualitative decrease in the intensity and breadth of ltbp3 expression at the heart tube arterial pole (Fig. 6C,D). Using quantitative PCR, we learned that nkx2.5 morphants express approximately half the number of ltbp3 transcripts (Fig. 6E), suggesting that nkx2.5 is required to maintain ltbp3 expression.
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lateral to the second and third somite (Grandel and Schulte-Merker, 1998), and RA is required while these somites are formed. Similarly, in the mouse embryo the forelimbs develop adjacent to somites 8-12, and limited maternal RA treatment that includes the development of the first 4-8 somites in Aldh1a2-mutant mice rescues initiation of the forelimb field (Mic et al., 2004). Considering the variation inherent to rescue studies in the mouse in general, and that most RA may not be cleared immediately, limb field induction in mice can be viewed as taking place concurrently with the emergence of flanking somites. This observation holds particularly true for the chick embryo, where forelimb induction has occurred by the 20-25 somite stage, and the wing bud develops adjacent to somites 15-20 (reviewed by Martin, 1998). We therefore propose a general mechanism by which somite formation and forelimb field induction are coupled through a window of RA responsiveness.
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defined, stereotype positions, and eventually, the lateral rectus EOM and the MAM express distinct markers (Couly et al., 1992; Gardner and Barald, 1992; Mootoosamy and Dietrich, 2002; Noden, 1983a; Wachtler and Jacob, 1986). In addition, the head mesoderm possesses positional information, which it can superimpose onto stray neural crest cells (Trainor and Krumlauf, 2000). Thus, it was equally possible that head myogenesis is controlled by intrinsic or extrinsic cues. Grafting fragments of head mesoderm into heterotopic locations showed, however, that head muscle differentiation and specification is controlled by signals from the local environment. Head mesoderm from midbrain or otic levels grafted to the level of the anterior hindbrain initiated myogenesis and expressed the lateral rectus markers in the same fashion as the endogenous muscle anlage on the control side. Conversely, when head mesoderm normally providing this muscle was moved to the anterior midbrain or to otic levels, then muscle development proceeded in accordance with the new position and the lateral rectus markers were not expressed. Thus, while the head mesoderm is bound to employ a myogenic programme distinct from myogenic programmes in the trunk, the onset of this programme and the specification of individual muscles rely on instructive cues from the environment.
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streak from HH3 (~12 hours) (Fig. 1A,B; supplementary material Fig. S1A-D). We devised a new protocol for in ovo subgerminal- cavity injection (supplementary material Fig. S1E-I) to modulate globally the activity of Wnt, TGFβ or FGF pathway before Brachyury expression. These three pathways are known to regulate both mesoderm induction and streak formation (Bertocchini et al., 2004; Harvey et al., 2010; Kimelman, 2006; Stern, 2004; Voiculescu et al., 2007). Control injection did not affect embryo morphology, growth rate or Brachyury expression (Fig. 1C, top). Wnt3a did not elicit strong effect on either streak morphology or Brachyury expression (supplementary material Fig. S2A). Activin A produced a drastic dorsalizing phenotype, with the axial marker Gsc expressed in the central epiblast as a pocket and weak Brachyury at its rim (supplementary material Fig. S2B-D). Activation of the FGF pathway (FGF4, Fig. 1C, middle and bottom) generated a ring of Brachyury-positive cells in the marginal zone. Induction by FGF4 was highly efficient (70/72; 97%), with the streak recognizable in 42% of the cases (Fig. 1C, middle) and absent in the remainder (Fig. 1C, bottom). Regardless of whether the streak formed or not, induced mesoderm precursors expressed the epithelial- mesenchymal transition (EMT) marker Snai2 (Fig. 1D) (Nieto et al., 1994) and gave rise to migratory mesoderm cells (supplementary material Fig. S3; Movie 1) as in normal gatrulation EMT (Nakaya et al., 2008). Growth of FGF4-injected embryos did not exceed HH7 (Fig. 1E), possibly owing to its pleiotropic effect on somitogenesis and axial elongation (Bénazéraf et al., 2010). Taken together, FGF injections (FGF4 in Fig. 1C, and FGF2 and
Mesoderm induction by FoxD3 is non-cell- autonomous and dependent on Nodal signaling The mesoderm-inducing activity of FoxD3 is identical to Smad2- activating members of the TGF family, including the Nodal- related genes required for mesoderm formation (Heasman, 2006; Schier and Shen, 2000). This suggested that FoxD3 may interact with a Smad2-activating pathway to induce mesoderm, either as an upstream regulator of ligand expression, or as a downstream mediator of the response to active Smad2. To assess the potential involvement of secreted factors in the response to FoxD3, the cell autonomy of mesoderm induction by FoxD3 was examined in dissociated animal explants. In this approach, explants prepared before the midblastula transition are dissociated into individual cells in calcium-free medium to prevent a response to zygotically expressed secreted factors (Sargent et al., 1986; Wilson and Melton, 1994). Control and FoxD3-expressing animal explants were prepared at the early blastula stage (stage 7), and intact or dissociated explants were examined for mesodermal gene expression at the gastrula stage. In intact explants, FoxD3 induced expression of Brachyury and MyoD, but mesodermal gene expression was not observed in dissociated explants (Fig. 6A). To further assess the autonomy of FoxD3 function in mesoderm induction, FoxD3 RNA was injected into a single animal pole blastomere at the 32-cell stage, and the distribution of mesodermal gene expression and FoxD3 protein was examined in gastrula explants (Fig. 6B). Brachyury expression was induced in a ring of cells adjacent to, but not overlapping a group of cells containing nuclear FoxD3 protein. Brachyury mRNA and FoxD3 protein were not observed in explants of uninjected embryos (data not shown).
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Endoderm and mesoderm can separate in various ways from ectoderm. The variability of the cellular processes raises the question, whether these so differently produced germ layers are really of the same evolutionary origin. One way to approach this question is to study genes involved in endoderm and mesoderm formation in different systems. The underlying assumption is that there is a conserved set of genes, that triggers the different mechanisms, that finally lead to the same result. Of course, the role of these genes in these processes could also have evolved convergently. Yet, transcription factors are particularly useful tools to examine this question, since there is no a priori reason, why a particular transcription factor regulates the expression of genes involved in the specification and differentiation of germ layers and their morphogenetic behavior. In contrast to genes coding for structural proteins specific of a particular structure, there is no functional constraint on the role of a given transcription factor in the generation of a structure. Thus, if we find common expression patterns in a number of distantly related organisms we must conclude that the common ancestor of these organisms also used this gene in this context, i.e. the function of the gene is homologous. Among the genes, that are commonly accepted as mesoderm markers and key players in mesoderm specification and pattern- ing, are those coding for the transcription factors , twist, snail, GATA factors and Brachyury . GATA factors appear to play crucial roles in specifying mesendoderm in early development, later specifying endoderm, when mesoderm separates from endoderm. Especially twist and snail contribute to mesoderm formation in protostomes and deuterostomes. The role of brachyury in mesoderm fomation is well established in vertebrates, and recent results also showed a contribution in mesoderm formation in protostomes. Many other genes are also important players in the formation of the inner germ
Serum response factor (SRF) is a MADS box-containing transcription factor that binds to a serum response element (SRE) found in the promoters of a variety of genes, including immediate early genes, neuronal genes and muscle genes (Shore and Sharrocks, 1995). SRF contains a highly conserved N-terminal DNA-binding and dimerization domain termed the MADS box – owing to its homology among yeast (MCM1, Agamous), plant (Deficiens) and vertebrate (SRF) proteins – and a C-terminal transactivation domain (Johansen and Prywes, 1993; Norman et al., 1988; Shore and Sharrocks, 1995). SRF controls cell growth and differentiation, neuronal transmission and muscle development, and functions by regulating the expression of its target genes (Carson et al., 2000; Castillo et al., 1997; Treisman, 1986). SRF-deficient mouse embryos display early embryonic lethality owing to the absence of mesodermal cells, and this has led to the proposal that SRF is required for mesoderm formation during mouse gastrulation (Arsenian et al., 1998). Interestingly, experiments using SRF –/–
Regulation of RNA metabolism is essential for a variety of developmental processes. The RNA-binding protein (RBP) Held out wing (HOW) is highly expressed in the mesoderm during early embryogenesis. HOW belongs to the STAR (signal transduction and activation of RNA) family (Vernet and Artzt, 1997), which includes the Caenorhabditis elegans homolog GLD-1, and the mammalian quaking (QKI, QK) protein. The STAR RBPs are essential for the control of transitional differentiation states – including the transition from mitosis to meiosis and sex-determination mediated by GLD-1 in C. elegans (Crittenden et al., 2002; Crittenden et al., 2003; Hansen and Schedl, 2006), and the maturation of Schwann cells in the PNS and oligodendrocytes in the CNS mediated by QKI in mammalian species (Ebersole et al., 1996; Hardy, 1998; Larocque and Richard, 2005). In the Drosophila embryo, HOW regulates heart-beat rate, mesoderm invagination, muscle-dependent tendon cell differentiation and glial maturation (Baehrecke, 1997; Nabel-Rosen et al., 1999; Zaffran et al., 1997). The how gene is differentially spliced into two isoforms, HOW(L) and HOW(S), which share the same signature of the RNA-binding domain but differ at their C- terminal region. Although both HOW(L) and HOW(S) can bind the same mRNA target, they act in opposing directions; binding of HOW(L) to stripe mRNA at the 3 ⬘ UTR leads to mRNA degradation, whereas the binding of HOW(S) leads to the stabilization of stripe mRNA (Nabel-Rosen et al., 2002). In addition
Gap junctions have been reported to function in LR determination in several vertebrate models (Levin and Mercola, 1998; Levin and Mercola, 1999). In rabbits, gap junctions are used to prevent signal transfer from the node to the right LPM in cooperation with Fgf8 signaling (Feistel and Blum, 2008). Although, in this case, the tissues responsible for the gap junction communication were not clearly identified, Cx43 is expressed in the endoderm as well as in the mesoderm and ectoderm of the rabbit embryo, similar to the mouse (Fig. 6; supplementary material Fig. S3). These data suggest that a role for endoderm cell gap junctions in mediating signals from the node to the LPM is conserved in mammals.
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Here, we first provide an overview of the pathways and proteins that regulate or mediate RA signalling during development, many of which appear to be highly conserved throughout vertebrate species. We then review the main functions of retinoid signalling during early embryonic development, first referring to the developing hindbrain as a system that has been most extensively studied with respect to RA functions and for which recent studies have refined our knowledge of the control of RA activity during rhombomeric segmentation. We further review extensive work that, over the last few years, has investigated how RA acts on progenitor cell populations in structures as diverse as the embryonic forebrain, the branchial apparatus and foregut derivatives, the neural plate and the posterior mesoderm during embryonic axial elongation. Understanding these functions and the underlying molecular events is of great importance, as retinoids are widely used in therapy and in many protocols for differentiating primary cultures or cell lines [including embryonic stem (ES) cells] into specific lineages (see Box 1). Retinoids thus hold promise for future use in stem cell- based therapy and regenerative medicine. Ongoing research will also guide more conventional clinical approaches, especially in the context of cancer chemoprevention or treatment (reviewed by Tang and Gudas, 2011).
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