Why we have (only) five fingers per hand: hox genes and the evolution of paired limbs

Development ◽  
1992 ◽  
Vol 116 (2) ◽  
pp. 289-296 ◽  
Author(s):  
C.J. Tabin
Keyword(s):  
Limb Development ◽  
Hox Genes ◽  
Expression Patterns ◽  
Limb Bud ◽  
Developmental Constraint ◽  
Limb Morphogenesis ◽  
Different Types ◽  
Embryonic Limb ◽  
Limb Pattern ◽  
Anterior Posterior

Limb development has long been a model system for studying vertebrate pattern formation. The advent of molecular biology has allowed the identification of some of the key genes that regulate limb morphogenesis. One important class of such genes are the homeobox-containing, or Hox genes. Understanding of the roles these genes play in development additionally provides insights into the evolution of limb pattern. Hox gene expression patterns divide the embryonic limb bud into five sectors along the anterior/posterior axis. The expression of specific Hox genes in each domain specifies the developmental fate of that region. Because there are only five distinct Hox-encoded domains across the limb bud there is a developmental constraint prohibiting the evolution of more than five different types of digits. The expression patterns of Hox genes in modern embryonic limb buds also gives clues to the shape of the ancestral fin field from which the limb evolved, hence elucidating the evolution of the tetrapod limb.

Ghox 4.7: a chick homeobox gene expressed primarily in limb buds with limb-type differences in expression

Development ◽  
1991 ◽  
Vol 112 (3) ◽  
pp. 791-806 ◽  
Author(s):  
S. Mackem ◽  
K.A. Mahon
Keyword(s):  
Expression Patterns ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Limb Bud ◽  
Limb Buds ◽  
Limb Morphogenesis ◽  
Degenerate Oligonucleotide ◽  
Polymerase Chain ◽  
Anterior Posterior

Homeobox genes play a key role in specifying the segmented body plan of Drosophila, and recent work suggests that at least several homeobox genes may play a regulatory role during vertebrate limb morphogenesis. We have used degenerate oligonucleotide primers from highly conserved domains in the homeobox motif to amplify homeobox gene segments from chick embryo limb bud cDNAs using the polymerase chain reaction. Expression of a large number of homeobox genes (at least 17) is detected using this approach. One of these genes contains a novel homeobox loosely related to the Drosophila Abdominal B class, and was further analyzed by determining its complete coding sequence and evaluating its expression during embryogenesis by in situ hybridization. Based on sequence and expression patterns, we have designated this gene as Ghox 4.7 and believe that it is the chick homologue of the murine Hox 4.7 gene (formerly Hox 5.6). Ghox 4.7 is expressed primarily in limb buds during development and shows a striking spatial restriction to the posterior zone of the limb bud, suggesting a role in specifying anterior-posterior pattern formation. In chick, this gene also displays differences in expression between wing and leg buds, raising the possibility that it may participate in specifying limb-type identity.

scholarly journals Multi-view light-sheet imaging and tracking with the MaMuT software reveals the cell lineage of a direct developing arthropod limb

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Carsten Wolff ◽  
Jean-Yves Tinevez ◽  
Tobias Pietzsch ◽  
Evangelia Stamataki ◽  
Benjamin Harich ◽  
...  
Keyword(s):  
Limb Development ◽  
Expression Patterns ◽  
Cell Lineage ◽  
Light Sheet ◽  
Limb Bud ◽  
Spatial Modulation ◽  
Spatiotemporal Resolution ◽  
Cell Behaviors ◽  
Light Sheet Microscopy ◽  
Anterior Posterior

During development, coordinated cell behaviors orchestrate tissue and organ morphogenesis. Detailed descriptions of cell lineages and behaviors provide a powerful framework to elucidate the mechanisms of morphogenesis. To study the cellular basis of limb development, we imaged transgenic fluorescently-labeled embryos from the crustacean Parhyale hawaiensis with multi-view light-sheet microscopy at high spatiotemporal resolution over several days of embryogenesis. The cell lineage of outgrowing thoracic limbs was reconstructed at single-cell resolution with new software called Massive Multi-view Tracker (MaMuT). In silico clonal analyses suggested that the early limb primordium becomes subdivided into anterior-posterior and dorsal-ventral compartments whose boundaries intersect at the distal tip of the growing limb. Limb-bud formation is associated with spatial modulation of cell proliferation, while limb elongation is also driven by preferential orientation of cell divisions along the proximal-distal growth axis. Cellular reconstructions were predictive of the expression patterns of limb development genes including the BMP morphogen Decapentaplegic.

Crustacean Limb Morphogenesis during Normal Development and Regeneration

2020 ◽  
pp. 46-79
Author(s):  
Anastasios Pavlopoulos ◽  
Carsten Wolff
Keyword(s):  
Limb Development ◽  
Hox Genes ◽  
Expression Patterns ◽  
Limb Regeneration ◽  
Daphnia Pulex ◽  
Experimental Models ◽  
Full Potential ◽  
Loss Of Function ◽  
Embryonic Limb ◽  
Cellular Behaviors

Crustaceans have been favored in developmental biology for the study of the diversification of body plans and their associated appendages, which exhibit remarkable diversity within and between species. Until recently, because of technical limitations, crustacean studies were restricted in scope to the comparison of appendage morphologies and expression patterns of candidate limb patterning genes already known from classic developmental animal models. To remedy this limitation and explore their full potential, a few select crustacean experimental models have been reinforced with powerful genomic and transcriptomic resources, new methods for forward and reverse genetic investigations, and for live imaging of entire embryos, or cell and tissue-specific markers, with exceptional spatial and temporal resolution. These models include the malacostracan amphipod Parhyale hawaiensis and the branchiopod cladocerans Daphnia magna and Daphnia pulex, which display collectively all the different uniramous, biramous, and phyllopodous crustacean limb types. Within the past couple years, important discoveries have been made on the molecular and cellular basis of embryonic limb development and postembryonic limb regeneration. In Parhyale alone, gain and loss-of-function studies of Hox genes have revealed the combinatorial logic used by these genes for appendage specialization, whereas the reconstruction of single-cell-resolution fate maps of developing and regenerating appendages have identified the lineage restrictions and cellular behaviors driving both morphogenetic processes. Century-old questions regarding the conservation and divergence of appendage patterning mechanisms across arthropods and bilaterians, or how these mechanisms can be used and reused throughout the lifetime of an organism, can now be addressed productively with crustaceans.

Hox genes and growth: early and late roles in limb bud morphogenesis

Development ◽  
1994 ◽  
Vol 1994 (Supplement) ◽  
pp. 181-186
Author(s):  
Bruce A. Morgan ◽  
Cliff Tabin
Keyword(s):  
Limb Development ◽  
Hox Genes ◽  
Limb Bud ◽  
Limb Mesenchyme ◽  
Positional Identity ◽  
Limb Morphogenesis ◽  
Combined Action ◽  
Level Of Understanding ◽  
Hox Clusters ◽  
Hoxd Gene

In recent years, molecular analysis has led to the identification of some of the key genes that control the morphogenesis of the developing embryo. Detailed functional analysis of these genes is rapidly leading to a new level of understanding of how embryonic form is regulated. Understanding the roles that these genes play in development can additionally provide insights into the evolution of morphology. The 5′ genes of the vertebrate Hox clusters are expressed in complex patterns during limb morphogenesis. Various models suggest that the Hoxd genes specify positional identity along the anteroposterior (A-P) axis of the limb. Close examination of the pattern of Hoxd gene expression in the limb suggests that a distinct combination of Hoxd gene expressed in different digit primordia is unlikely to specify each digit independently. The effects of altering the pattern of expression of the Hoxd-11 gene at different times during limb development indicate that the Hoxd genes have separable early and late roles in limb morphogenesis. In their early role, the Hoxd genes are involved in regulating the growth of the undifferentiated limb mesenchyme. Restriction of the expression of successive 5′ Hoxd genes to progressively more posterior regions of the bud results in the asymmetric outgrowth of the limb mesenchyme. Later in limb development, Hoxd genes also regulate the maturation of the nascent skeletal elements. The degree of overlap in function between different Hoxd genes may be different in these early and late roles. The combined action of many Hox genes on distinct developmental processes contribute to pattern asymmetry along the A-P axis.

Analysis of Hox gene expression in the chick limb bud

Development ◽  
1996 ◽  
Vol 122 (5) ◽  
pp. 1449-1466 ◽  
Author(s):  
C.E. Nelson ◽  
B.A. Morgan ◽  
A.C. Burke ◽  
E. Laufer ◽  
E. DiMambro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Hind Limb ◽  
Hox Genes ◽  
Expression Patterns ◽  
Limb Bud ◽  
Posterior Portion ◽  
Hox Gene ◽  
Hoxd Gene

The vertebrate Hox genes have been shown to be important for patterning the primary and secondary axes of the developing vertebrate embryo. The function of these genes along the primary axis of the embryo has been generally interpreted in the context of positional specification and homeotic transformation of axial structures. The way in which these genes are expressed and function during the development of the secondary axes, particularly the limb, is less clear. In order to provide a reference for understanding the role of the Hox genes in limb patterning, we isolated clones of 23 Hox genes expressed during limb development, characterized their expression patterns and analyzed their regulation by the signalling centers which pattern the limb. The expression patterns of the Abd-B-related Hoxa and Hoxd genes have previously been partially characterized; however, our study reveals that these genes are expressed in patterns more dynamic and complex than generally appreciated, only transiently approximating simple, concentric, nested domains. Detailed analysis of these patterns suggests that the expression of each of the Hoxa and Hoxd genes is regulated in up to three independent phases. Each of these phases appears to be associated with the specification and patterning of one of the proximodistal segments of the limb (upper arm, lower arm and hand). Interestingly, in the last of these phases, the expression of the Hoxd genes violates the general rule of spatial and temporal colinearity of Hox gene expression with gene order along the chromosome. In contrast to the Abd-B-related Hoxa and Hoxd genes, which are expressed in both the fore and hind limbs, different sets of Hoxc genes are expressed in the two limbs. There is a correlation between the relative position of these genes along the chromosome and the axial level of the limb bud in which they are expressed. The more 3′ genes are expressed in the fore limb bud while the 5′ genes are expressed in the hind limb bud; intermediate genes are transcribed in both limbs. However, there is no clear correlation between the relative position of the genes along the chromosome and their expression domains within the limb. With the exception of Hoxc-11, which is transcribed in a posterior portion of the hind limb, Hoxc gene expression is restricted to the anterior/proximal portion of the limb bud. Importantly, comparison of the distributions of Hoxc-6 RNA and protein products reveals posttranscriptional regulation of this gene, suggesting that caution must be exercised in interpreting the functional significance of the RNA distribution of any of the vertebrate Hox genes. To understand the genesis of the complex patterns of Hox gene expression in the limb bud, we examined the propagation of Hox gene expression relative to cell proliferation. We find that shifts in Hox gene expression cannot be attributed to passive expansion due to cell proliferation. Rather, phase-specific Hox gene expression patterns appear to result from a context-dependent response of the limb mesoderm to Sonic hedgehog. Sonic hedgehog (the patterning signal from the Zone of Polarizing Activity) is known to be able to activate Hoxd gene expression in the limb. Although we find that Sonic hedgehog is capable of initiating and polarizing Hoxd gene expression during both of the latter two phases of Hox gene expression, the specific patterns induced are not determined by the signal, but depend upon the temporal context of the mesoderm receiving the signal. Misexpression of Sonic hedgehog also reveals that Hoxb-9, which is normally excluded from the posterior mesenchyme of the leg, is negatively regulated by Sonic hedgehog and that Hoxc-11, which is expressed in the posterior portion of the leg, is not affected by Sonic hedgehog and hence is not required to pattern the skeletal elements of the lower leg.

Conservation of Pitx1 expression during amphibian limb morphogenesis

2006 ◽  
Vol 84 (2) ◽  
pp. 257-262 ◽  
Author(s):  
W Y Chang ◽  
F KhosrowShahian ◽  
M Wolanski ◽  
R Marshall ◽  
W McCormick ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Xenopus Laevis ◽  
Expression Patterns ◽  
Limb Bud ◽  
Eleutherodactylus Coqui ◽  
Limb Buds ◽  
Homeodomain Transcription Factor ◽  
Limb Morphogenesis ◽  
Pelvic Limb

In contrast to the pattern of limb emergence in mammals, chicks, and the newt N. viridescens, embryos such as Xenopus laevis and Eleutherodactylus coqui initiate pelvic limb buds before they develop pectoral ones. We studied the expression of Pitx1 in X. laevis and E. coqui to determine if this paired-like homeodomain transcription factor directs differentiation specifically of the hindlimb, or if it directs the second pair of limbs to form, namely the forelimbs. We also undertook to determine if embryonic expression patterns were recapitulated during the regeneration of an amputated limb bud. Pitx1 is expressed in hindlimbs in both X. laevis and E. coqui, and expression is similar in both developing and regenerating limb buds. Expression in hindlimbs is restricted to regions of proliferating mesenchyme.Key words: regeneration, Xenopus laevis, limb bud, Pitx1 protein, specification.

Retinoic acid signaling is required during early chick limb development

Development ◽  
1996 ◽  
Vol 122 (5) ◽  
pp. 1385-1394 ◽  
Author(s):  
J.A. Helms ◽  
C.H. Kim ◽  
G. Eichele ◽  
C. Thaller
Keyword(s):  
Retinoic Acid ◽  
Limb Development ◽  
Acid Synthesis ◽  
Apical Ectodermal Ridge ◽  
Limb Bud ◽  
Retinoid Receptor ◽  
Limb Morphogenesis ◽  
Wing Bud ◽  
Zone Of Polarizing Activity

In the chick limb bud, the zone of polarizing activity controls limb patterning along the anteroposterior and proximodistal axes. Since retinoic acid can induce ectopic polarizing activity, we examined whether this molecule plays a role in the establishment of the endogenous zone of polarizing activity. Grafts of wing bud mesenchyme treated with physiologic doses of retinoic acid had weak polarizing activity but inclusion of a retinoic acid-exposed apical ectodermal ridge or of prospective wing bud ectoderm evoked strong polarizing activity. Likewise, polarizing activity of prospective wing mesenchyme was markedly enhanced by co-grafting either a retinoic acid-exposed apical ectodermal ridge or ectoderm from the wing region. This equivalence of ectoderm-mesenchyme interactions required for the establishment of polarizing activity in retinoic acid-treated wing buds and in prospective wing tissue, suggests a role of retinoic acid in the establishment of the zone of polarizing activity. We found that prospective wing bud tissue is a high-point of retinoic acid synthesis. Furthermore, retinoid receptor-specific antagonists blocked limb morphogenesis and down-regulated a polarizing signal, sonic hedgehog. Limb agenesis was reversed when antagonist-exposed wing buds were treated with retinoic acid. Our results demonstrate a role of retinoic acid in the establishment of the endogenous zone of polarizing activity.

Sonic hedgehog is not required for polarising activity in the Doublefoot mutant mouse limb bud

Development ◽  
1998 ◽  
Vol 125 (3) ◽  
pp. 351-357 ◽  
Author(s):  
C. Hayes ◽  
J.M. Brown ◽  
M.F. Lyon ◽  
G.M. Morriss-Kay
Keyword(s):  
Gene Expression ◽  
Limb Development ◽  
Target Genes ◽  
Anterior Part ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Mutant Gene ◽  
Limb Bud ◽  
Active Constituent ◽  
Limb Buds

The mouse mutant Doublefoot (Dbf) shows preaxial polydactyly of all four limbs. We have analysed limb development in this mutant with respect to morphogenesis, gene expression patterns and ectopic polarising activity. The results reveal a gain-of-function mutation at a locus that mediates pattern formation in the developing limb. Shh expression is identical with that of wild-type embryos, i.e. there is no ectopic expression. However, mesenchyme from the anterior aspects of Dbf/+ mutant limb buds, when transplanted to the anterior side of chick wing buds, induces duplication of the distal skeletal elements. Mid-distal mesenchymal transplants from early, but not later, Dbf/+ limb buds are also able to induce duplication. This demonstration of polarising activity in the absence of Shh expression identifies the gene at the Dbf locus as a new genetic component of the Shh signalling pathway, which (at least in its mutated form) is able to activate signal transduction independently of Shh. The mutant gene product is sufficient to fulfil the signalling properties of Shh including upregulation of the direct Shh target genes Ptc and Gli, and induction of the downstream target genes Bmp2, Fgf4 and Hoxd13. The expression domains of all these genes extend from their normal posterior domains into the anterior part of the limb bud without being focused on a discrete ectopic site. These observations dissociate polarising activity from Shh gene expression in the Dbf/+ limb bud. We suggest that the product of the normal Dbf gene is a key active constituent of the polarising region, possibly acting in the extracellular compartment.

scholarly journals Transcriptional Trajectories in Mouse Limb Buds Reveal the Transition from Anterior-Posterior to Proximal-Distal Patterning at Early Limb Bud Stage

2020 ◽  
Vol 8 (4) ◽  
pp. 31
Author(s):  
Ines Desanlis ◽  
Rachel Paul ◽  
Marie Kmita
Keyword(s):  
Global Change ◽  
Hox Genes ◽  
Limb Bud ◽  
Temporal Expression ◽  
Distal Limb ◽  
Limb Patterning ◽  
Previous Evidence ◽  
Limb Mesenchyme ◽  
Mouse Limb ◽  
Anterior Posterior

Limb patterning relies in large part on the function of the Hox family of developmental genes. While the differential expression of Hox genes shifts from the anterior–posterior (A–P) to the proximal–distal (P–D) axis around embryonic day 11 (E11), whether this shift coincides with a more global change of A–P to P–D patterning program remains unclear. By performing and analyzing the transcriptome of the developing limb bud from E10.5 to E12.5, at single-cell resolution, we have uncovered transcriptional trajectories that revealed a general switch from A–P to P–D genetic program between E10.5 and E11.5. Interestingly, all the transcriptional trajectories at E10.5 end with cells expressing either proximal or distal markers suggesting a progressive acquisition of P–D identity. Moreover, we identified three categories of genes expressed in the distal limb mesenchyme characterized by distinct temporal expression dynamics. Among these are Hoxa13 and Hoxd13 (Hox13 hereafter), which start to be expressed around E10.5, and importantly the binding of the HOX13 factors was observed within or in the neighborhood of several of the distal limb genes. Our data are consistent with previous evidence suggesting that the transition from the early/proximal to the late/distal transcriptome of the limb mesenchyme largely relies on HOX13 function. Based on these results and the evidence that HOX13 factors restrict Hoxa11 expression to the proximal limb, in progenitor cells of the zeugopod, we propose that HOX13 act as a key determinant of P–D patterning.

scholarly journals A re-inducible gap gene cascade patterns the anterior-posterior axis of insects in a threshold-free fashion

2018 ◽  
Author(s):  
Alena Boos ◽  
Jutta Distler ◽  
Heike Rudolf ◽  
Martin Klingler ◽  
Ezzat El-Sherif
Keyword(s):  
Gene Network ◽  
Hox Genes ◽  
Expression Patterns ◽  
Fruit Fly ◽  
Regulation Mechanism ◽  
Gap Gene ◽  
Speed Regulation ◽  
Gap Genes ◽  
Anterior Posterior ◽  
Anterior Posterior Axis

AbstractGap genes mediate the division of the anterior-posterior axis of insects into different fates through regulating downstream hox genes. Decades of tinkering the segmentation gene network of the long-germ fruit fly Drosophila melanogaster led to the conclusion that gap genes are regulated (at least initially) through a threshold-based French Flag model, guided by both anteriorly- and posteriorly-localized morphogen gradients. In this paper, we show that the expression patterns of gap genes in the intermediate-germ beetle Tribolium castaneum are mediated by a threshold-free ‘Speed Regulation’ mechanism, in which the speed of a genetic cascade of gap genes is regulated by a posterior gradient of the transcription factor Caudal. We show this by re-inducing the leading gap gene (namely, hunchback) resulting in the re-induction of the gap gene cascade at arbitrary points in time. This demonstrates that the gap gene network is self-regulatory and is primarily under the control of a posterior speed regulator in Tribolium and possibly all insects.

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