Integrative and Comparative Biology Advance Access originally published online on August 8, 2007
Integrative and Comparative Biology 2007 47(3):382-389; doi:10.1093/icb/icm082
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Watch-ing out for chick limb development
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal
Correspondence: 1E-mail: ipalmeirim{at}ecsaude.uminho.pt
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Synopsis |
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Time control is a crucial issue during embryonic development. Nevertheless, little is known about how embryonic cells measure time. Until recently, the only molecular clock known to operate during vertebrate embryonic development was the somitogenesis clock, exclusively functioning in coordinating the precise timing of each new pair of somites formed from the presomitic mesoderm. We have recently evidenced that a similar molecular clock also underlies the timing at which autopod chondrogenic precursors are laid down to form a skeletal limb element. In addition, we herein suggest that the molecular clock is not the only parallelism that can be established between somitogenesis and limb-bud development. In an evolutionary perspective, we support the previously proposed idea that the molecular mechanisms involved in the segmentation of the body axis may have been partially reused in the mesoderm of the lateral plate, thereby allowing the emergence of paired appendages.
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Introduction |
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Growth and patterning of the vertebrate tetrapod limb has been a subject of intensive investigation for about three decades (Niswander 2003
). Limb buds form at specific positions along the axis of the body of an embryo. At presumptive limb levels, cells of the lateral plate mesoderm (LPM) proliferate under the epidermal tissue, initiating the formation of growing buds (Searls and Janners 1971; Chevallier et al. 1977; Christ et al. 1977). Later on, this mesenchyme gives rise to skeletogenic precursors, among other cell types, while muscle precursor cells invade the limb upon delamination from the lateral edges of the nearby somites (Buckingham et al. 2003). Three orthogonal axes describe the anatomy of the limb: proximal–distal (p–d), from the shoulder to the fingertips; anterior–posterior (a–p), from the thumb to the little finger; and the dorsal–ventral (d–v), from the back of the hand to the palm. The limb skeleton is formed by a distinct number of bones with a characteristic size and shape that are laid down along the p–d axis—humerus (stylopod), ulna and radius (zeugopod), metacarpals, and phalanges (autopod)—as the limb bud grows. P–d outgrowth is controlled by cells of the apical ectodermal ridge (AER), a specialized ectodermal structure that runs along the length of the distal tip of the limb bud and that expresses proteins belonging to the fibroblast growth factor (FGF) family of secreted proteins (reviewed by Martin 1998). The intracellular responses to FGFs are mediated by the MAPK signal-transduction cascade (Javerzat et al. 2002). In 2003, Kawakami and colleagues found MAPK phosphatase 3 (mkp3), a gene encoding a negative regulator of the MAPK/ERK pathway (Groom et al. 1996; Mourey et al. 1996; Muda et al. 1996; Smith et al. 1997) to be a downstream factor of the FGF8 signalling pathway during limb bud development.
Among the three cardinal axes of the limb, the mechanisms that lead to specification of cell fate along the p–d axis are the least understood. Dudley and co-workers proposed that populations of cells giving rise to the different p–d skeletal structures of the limb are specified very early during limb-bud development—"early specification model." Later, already specified populations of cells differentiate sequentially giving rise first to the more proximal structures and forming the distal structures last (Dudley et al. 2002). Another paradigm to explain limb development along this axis, largely unmodified since its conception 30 years ago, is the "progress zone model" (Summerbell et al. 1973). According to this model, the time cells spend in the distal-most mesenchyme, defined as the progress zone (PZ), specifies their fate along the p–d axis. Cells in the PZ would change their positional value over time, this being fixed when they leave this zone (Summerbell et al. 1973). The cells that leave the PZ earlier give rise to the more proximal skeletal elements of the wing (humerus) and those leaving later give rise to the more distal ones (phalanges). This model suggests that a clock-like mechanism could be operating, measuring the time that these cells spend in the PZ.
Palmeirim et al. (1997) demonstrated the existence of a molecular clock underlying chick somitogenesis by showing that presomitic mesodermal (PSM) cells undergo several cycles of hairy1 gene expression, with a 90 min periodicity, corresponding to the time required to form one somite (Palmeirim et al. 1997). This oscillatory expression provided the first molecular evidence for a developmental clock linked to somitogenesis, in which both the segment number and the time of formation are extraordinarily constant and species-specific. This molecular clock operates in all vertebrate groups that have been studied and an increasing number of genes belonging to the FGF, Notch, and Wnt signaling pathways were found to have a cyclic behavior in the PSM cells (reviewed by Andrade et al. 2005; Freitas et al. 2005; Dequéant et al. 2006; Stern et al. 2006).
In the chick PSM, posterior FGF8 and anterior retinoic acid activities form two opposing gradients (Dubrulle et al. 2001; Diez del Corral et al. 2003). The confrontation of these gradients gives rise to the so-called determination front that moves posteriorly as the embryonic axis elongates (Dubrulle et al. 2001). When the determination front is experimentally shifted anteriorly by placing an FGF8-coated bead in the mid-PSM, smaller somites form. Conversely, FGF8 inhibition at the same level induces the formation of larger somites (Dubrulle et al. 2001). Thus, FGF8 maintains posterior PSM cells in an immature state, negatively regulating differentiation in chick PSM.
In summary, in the somitogenesis system, a molecular clock operates in the PSM and regulates the periodicity of the formation of the segmented elements (the somites) and a maturation wavefront controls the size of the elements that are formed. An interesting question thus arises: are the same molecular mechanisms used in other tissues to control the formation of different segmented structures?
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Hairy2 is cyclically expressed in the precursor cells of the autopod limb bones |
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SynopsisIntroduction Hairy2 is cyclically expressed... Cyclic hairy2 expression and...Notch signaling pathway in...Is there a wavefront...The clock in an...Final remarksAcknowledgmentsReferences |
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Hirata et al. (2002
) showed that periodic expression of Hes1 can be triggered in a variety of cultured cell lines in response to a serum shock, suggesting that the genes of the segmentation clock might play a role in other cell types and biological processes. In vivo, however, such oscillations of gene expression have only been reported in presomitic cells. Recently, we described the dynamic expression of hairy2 (the chick hes1 homologue) in the distal part of stage HH20-28 forelimb mesenchyme, in an area of undifferentiated chondrogenic precursor cells (Fig. 1). By performing in ovo microsurgery, we demonstrated that hairy2 expression is cyclic in phalanx chondrogenic precursors with a 6 h periodicity (Pascoal, Carvalho et al. 2007; Fig. 2). In contrast, hairy2 expression is never detected in the central core of the limb where the already-specified cartilaginous elements are localized, suggesting that cartilaginous precursor cells stop performing hairy2 expression cycles when they differentiate (Pascoal, Carvalho et al. 2007).
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We demonstrated that hairy2 is cyclically expressed in the distal mesenchyme of the limb with a 6 h periodicity (Pascoal, Carvalho et al. 2007
). Interestingly, the 6 h time-period is a multiple of the 1.5 h period reported for hairy2 in somite precursor cells. This is strikingly in accordance with the "clock and trail model" proposed by Kerszberg and Wolpert (2000), which concentrates on the somitogenesis clock and in which period-doubling oscillations can arise from an oligomerization mechanism between transcription factors that act either by activating or inhibiting genes, including themselves. These authors argue for the existence of cyclic gene expression with a period different from 1.5 h, but multiples of this value, and these cycles could specify hemi-somites (period of 45 min), somites (1.5 h), or even pairs of somites (3 h) (Kerszberg and Wolpert, 2000). During somitogenesis, each cycle of expression of a molecular clock gene underlies the formation of a new pair of somites and both events take 1.5 h. In the limb, the formation time of skeletal elements was unknown.
By measuring the time between the appearances of two consecutive gdf5 (joint marker) stripes of expression corresponding to the second and third joint of digit 3, we found that the formation time of the second phalanx is 12 h (Pascoal, Carvalho et al. 2007). Previous work suggested that each of the seven limb bone primordials take about the same length of time to be laid down (Wolpert et al. 1975). If this is the case, the formation of the entire set of seven limb elements would take 3.5 days, which is in accordance with the experimentally-determined time required to form a chick forelimb (3–4 days; Hamburger and Hamilton 1951).
During somite formation, each PSM cell undergoes many molecular clock gene cycles before escaping the influence of FGF8 and becoming committed to incorporate a somite. Similarly, we propose that autopod chondrogenic precursor cells go through several cycles of hairy2 expression until they incorporate a cartilaginous primordial of an autopod bone and that two hairy2 cycles represent the time period required to form an autopod skeletal element (Pascoal, Carvalho et al. 2007; Fig. 3). Hence, this study unveils the existence of a limb molecular clock operating during autopod p–d outgrowth and patterning, with a specific time period that can be correlated with the time required to form an autopod skeletal element.
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Cyclic hairy2 expression and the acquisition of temporal information |
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Top
SynopsisIntroductionHairy2 is cyclically expressed...Cyclic hairy2 expression and...Notch signaling pathway in...Is there a wavefront...The clock in an...Final remarksAcknowledgmentsReferences |
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The major difference between the "progress zone model" (Summerbell et al. 1973
) and the "early specification model" (Dudley et al. 2002) is the timing at which p–d specification takes place. The progress zone model proposes sequential p–d specification, while the early specification model suggests that all cell fates are already specified within the early limb bud and that progressive formation of p–d segments results from a temporally coordinated expansion of the progenitor populations in each domain (Dudley et al. 2002). In light of the new data, we propose that cells in the proliferative region of the limb can record the number of hairy2 oscillations that they perform and thus acquire a temporal value. This temporal value could be (1) translated in positional value, in agreement with the progress zone model or (2) it could establish the expansion time for the cell populations already specified according to the early specification model. Thus, the proposal that hairy2 expression provides temporal information is compatible with either model (Pascoal, Carvalho et al. 2007). |
Notch signaling pathway in p–d limb outgrowth |
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Studies in both chick and mouse embryos provide data compatible with a role for the Notch signaling pathway in the development of the distal mesenchyme of the forelimb (Table 1). Limb phenotypes of mouse embryos lacking Notch1 or Serrate2/Jagged2 (expressed in both chick and mouse AER) in the AER implicate Notch signaling in the development of the AER and in interdigital apoptosis, possibly precluding a role for these particular genes in the molecular clock machinery of the limb bud (chick: Hayashi et al. 1996
; Myat et al. 1996; mouse: Shawber et al. 1996; Sidow et al. 1997; Jiang et al. 1998; Francis et al. 2005; Pan et al., 2005). In contrast, Notch2, and its ligand Serrate1/Jagged1, are coexpressed in the distal mesenchyme of the limb, rather than in the AER, both in chicks (Hayashi et al. 1996; Myat et al. 1996) and in mice (Shawber et al. 1996; Francis et al. 2005; McGlinn et al. 2005). Unfortunately, both Notch2 and Serrate1/Jagged1-null mouse mutants die in utero by E11.5, preventing determination of the function of these genes in limb mesenchyme (Hamada et al. 1999; Xue et al. 1999). Notch downstream targets hairy1 and hairy2 in the chick (Vasiliauskas et al. 2003; Pascoal, Carvalho et al. 2007 and our unpublished data) and Hes1, Hey1 in the mouse (McGlinn et al. 2005) are coexpressed with Notch2 and Serrate1/Jagged1 in the distal mesenchyme of the limb, indicating an activation and a putative function of this signaling pathway. In agreement, studies of the misexpression of hairy1 in the chick implicate Notch pathway in the regulation of overall limb size (Vasiliauskas et al. 2003). Since no skeletal analysis has been performed for the Hes1- and Hey1-null mouse mutant (Ishibashi et al. 1995; Fischer et al. 2004), we do not know the role these genes play in skeletal limb-bud development. Moreover, while evidence has been provided that Notch can function nonautonomously across germ layers (Baker and Schubiger 1996), it is possible that different combinations of these receptors/ligands may mediate an interaction between the AER and the mesenchyme. Interestingly, overactivation of Notch signaling in the limb ectoderm produced a dramatic effect on limb skeletal development, involving extensive hind limb truncations, including complete or partial loss of zeugopods and autopods (Pan et al. 2005). Finally, loss of both presenilins from the mesenchyme of the mouse limb gives rise to mutant embryos with clenched forelimb digits, truncated digits, and digits with some distal phalanges missing, leading the authors to propose that a deficiency of presenilin in mesenchyme could affect endochondral skeletal differentiation (Pan et al. 2005).
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In conclusion, data both from the chick and the mouse suggest a possible role of the Notch signaling pathway in the distal mesenchyme of the limb, possibly through the receptor/ligand duo Notch2/Serrate1, as has been previously proposed (Hayashi et al. 1996
; Shawber et al. 1996; Pan et al. 2005). Our recent report of the cyclic expression of hairy2, a transcription factor downstream of Notch, allowing the identification of a molecular clock operating in the distal mesenchyme of the limb, reinforces this possibility (Pascoal, Carvalho et al. 2007). To further evaluate the role of the Notch signaling pathway in the distal mesenchyme of the limb, it is crucial to produce KO mice for Notch 2 and Jagged1/Serrate1 conditional for the distal limb mesenchyme and to perform further studies of misexpression of these and other genes in the chick embryo. |
Is there a wavefront in the limb bud? |
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In 2001, Dubrulle et al. (2001
) demonstrated a gradient of fgf8 transcripts starting from the embryo tail bud and fading in the direction of the uppermost part of the PSM. This graded distribution of fgf8 mRNA was shown to result from progressive mRNA decay, rather than from different transcriptional levels (Dubrulle and Pourquié 2004). Recently, we have shown that mkp3, a downstream effector of FGF8 (Kawakami et al. 2003), has a graded distribution of its transcripts in the mesenchyme of the limb bud, beginning in the most distal part of the limb (underneath the AER) and fading out in the direction of the more proximal part of the limb (Pascoal, Andrade et al. 2007). To further characterize this gradient, an intronic probe for mkp3 was constructed and the distribution of mkp3 nascent transcripts observed. The cells recognized by the intronic probe were restricted to the more distal part of the limb, mimicking the effect obtained with the intronic fgf8 probe in the PSM (Dubrulle and Pourquié 2004). This result demonstrates that the graded distribution of mkp3 in distal limb mesenchyme is a result of mRNA decay (Pascoal, Andrade et al. 2007).
These results led us to propose that the graded mkp3 expression pattern in the chick limb bud might result from RNA decay as follows: (1) the FGF8 protein produced in the AER induces mkp3 expression at the distal part of the limb; (2) as the limb bud grows the cells progressively move away from the FGF8 source; (3) once they are distant from the AER, the transcription of the mkp3 is no longer induced and the mRNA molecules still present in these cells decay over time, giving rise to a spatial gradient of mRNA expression in the limb bud (Pascoal, Andrade et al. 2007).
The gradient of mkp3 mRNA observed in chick wing bud corresponds to a gradient of Fgf8 activity, equivalent to that present in the chick presomitic mesoderm. Future work should clarify whether a wavefront is also involved in the establishment of the size of the limb bones.
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The clock in an evolutionary perspective |
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The acquisition of paired appendages was a main evolutionary advance for locomotion in vertebrates. The tetrapod forelimb bud is considered the vertebrate homologue of the zebrafish pectoral fin bud, since they share structural organization and repertoires of gene expression (Grandel and Schulte-Merker 1998
), suggesting that the paired appendages are conserved among species. Thus, the chick limb-bud molecular clock could also be operative in the limbs/fins of other species.
The first vertebrate fossils that were discovered lack paired fins, but show brawny median fins (Coates 1994; Zhang and Hou 2004), implying that mechanisms of fin development were first gathered in the midline (Freitas et al. 2006). Freitas and co-workers (2006) studied this possibility and showed that the development of the median fin in sharks involves the same genetic programs that operate in paired appendages. By using molecular markers for different cell types, they showed that median fins arise predominantly from somitic mesoderm, whereas paired appendages develop from the mesoderm of the lateral plate. These results suggest that the molecular mechanisms used for fin development originated in the somitic mesoderm of the first vertebrates and the origin of paired appendages was associated with relocation of these mechanisms to the lateral plate mesoderm (Freitas et al. 2006). Combining these results with the discovery of a molecular clock in the chick limb bud, we consider the molecular clock to be a constituent of the molecular program of the somitic mesoderm that was reused, thereby allowing the emergence of the paired appendages from the mesoderm of the lateral plate.
The forelimb of whales and dolphins presents hyperphalangy (supernumerary finger bones). One of the developmental bases proposed for this terminal addition of extra phalanges is that the limb outgrowth controlled by the AER may be prolonged by a shift in timing or heterochrony (Richardson and Oelschläger 2002). Richardson and Oelschläger (2002) showed that in the spotted dolphin Stenella attenuate, hyperphalangy was evident on digits II and III. Histological analysis has shown that the apical ectoderm was thickened into a cap that persists on digits II and III at stages when it had disappeared from other digits (Richardson and Oelschläger 2002). This implies that the cells at the tip of the limb are maintained in an undifferentiated state longer than are those in the other digits. This could indicate that the molecular clock genes would undergo expression cycles more times than in other digits. This could be a complementary explanation for the supernumerary phalanges formed in these two particular digits of the dolphin.
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Final remarks |
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The studies reported here allow us to propose a certain degree of parallelism between somitogenesis and limb bud development. Both tissues comprise a zone in which cells are maintained in an undifferentiated state (posterior PSM and distal limb mesenchyme). In addition, in the chick PSM, anterior retinoic acid and posterior FGF8 activities form two opposing gradients (Diez del Corral et al. 2003
) and the same happens during limb bud development in which retinoic acid synthesis and signaling is restricted to the proximal limb by FGF activity (Mercander et al. 2000). Moreover, in both limb and PSM, a molecular clock operates, regulating the periodicity of structure formation. Finally, we propose the possibility that a wavefront could be present in the distal limb mesenchyme in a way reminiscent of the one in the PSM. Our data provides further support for the previously proposed idea that the molecular program used for a–p axis segmentation of the vertebrate body might be partially reused in the outgrowth of vertebrate limbs. The discovery of the limb molecular clock unveiled a new mechanism in limb bud development. Taken together, the studies reviewed here have opened a completely novel line of investigation into limb development that could be further extrapolated to several developmental processes. Much work, however, must be performed before the machinery of this clock becomes completely understood.
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Acknowledgments |
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We wish to thank Leonor Saúde, Fernanda Bajanca e Raquel P. Andrade for critical reading of the article. Financial support was provided by FCT/FEDER (POCTI/BCI/42040/2001) and by the EU/FP6-Network of Excellence-Cells into Organs. S.P. (SFRH/BPD/26638/2006) was supported by FCT, Portugal.
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Footnotes |
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From the symposium "Linking Genes and Morphology in Vertebrates" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3–7, 2007, at Phoenix, Arizona.
2Present address: Instituto Gulbenkian de Ciência, Centro de Biologia do Desenvolvimento, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal. 
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