scholarly journals Manifestation of the Limb Prepattern: Limb Development in the Absence of Sonic Hedgehog Function

2001 ◽  
Vol 236 (2) ◽  
pp. 421-435 ◽  
Author(s):  
Chin Chiang ◽  
Ying Litingtung ◽  
Matthew P. Harris ◽  
B.Kay Simandl ◽  
Yina Li ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Limb Development

Limb deformity proteins: role in mesodermal induction of the apical ectodermal ridge

Development ◽  
1997 ◽  
Vol 124 (1) ◽  
pp. 133-139 ◽  
Author(s):  
J. Kuhlman ◽  
L. Niswander
Keyword(s):  
Sonic Hedgehog ◽  
Limb Development ◽  
Apical Ectodermal Ridge ◽  
Primary Defect ◽  
Limb Deformity ◽  
Normal Morphology ◽  
Fibroblast Growth Factor 8 ◽  
Skeletal Pattern ◽  
Two Phases ◽  
And Function

During early limb development, distal tip ectoderm is induced by the underlying mesenchyme to form the apical ectodermal ridge. Subsequent limb growth and patterning depend on reciprocal signaling between the mesenchyme and ridge. Mice that are homozygous for mutations at the limb deformity (ld) locus do not form a proper ridge and the anteroposterior axis of the limb is shortened. Skeletal analyses reveal shortened limbs that involve loss and fusion of distal bones and digits, defects in both anteroposterior and proximodistal patterning. Using molecular markers and mouse-chick chimeras we examined the ridge-mesenchymal interactions to determine the origin of the ld patterning defects. In the ld ridge, fibroblast growth factor 8 (Fgf8) RNA is decreased and Fgf4 RNA is not detected. In the ld mesenchyme, Sonic hedgehog (Shh), Evx1 and Wnt5a expression is decreased. In chimeras between ld ectoderm and wild-type mesenchyme, a ridge of normal morphology and function is restored, Fgf8 and Shh are expressed normally, Fgf4 is induced and a normal skeletal pattern arises. These results suggest that the ld mesenchyme is unable to induce the formation of a completely functional ridge. This primary defect causes a disruption of ridge function and subsequently leads to the patterning defects observed in ld limbs. We propose a model in which ridge induction requires at least two phases: an early competence phase, which includes induction of Fgf8 expression, and a later differentiation phase in which Fgf4 is induced and a morphological ridge is formed. Ld proteins appear to act during the differentiation phase.

Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4811-4823 ◽  
Author(s):  
J.J. Sanz-Ezquerro ◽  
C. Tickle
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Retroviral Vector ◽  
Cellular Mechanism ◽  
Limb Bud ◽  
Drug Induced ◽  
Signalling Molecule ◽  
Vertebrate Limb

The polarising region expresses the signalling molecule sonic hedgehog (Shh), and is an embryonic signalling centre essential for outgrowth and patterning of the vertebrate limb. Previous work has suggested that there is a buffering mechanism that regulates polarising activity. Little is known about how the number of Shh-expressing cells is controlled but, paradoxically, the polarising region appears to overlap with the posterior necrotic zone, a region of programmed cell death. We have investigated how Shh expression and cell death respond when levels of polarising activity are altered, and show an autoregulatory effect of Shh on Shh expression and that Shh affects cell death in the posterior necrotic zone. When we increased Shh signalling, by grafting polarising region cells or applying Shh protein beads, this led to a reduction in the endogenous Shh domain and an increase in posterior cell death. In contrast, cells in other necrotic regions of the limb bud, including the interdigital areas, were rescued from death by Shh protein. Application of Shh protein to late limb buds also caused alterations in digit morphogenesis. When we reduced the number of Shh-expressing cells in the polarising region by surgery or drug-induced killing, this led to an expansion of the Shh domain and a decrease in the number of dead cells. Furthermore, direct prevention of cell death using a retroviral vector expressing Bcl2 led to an increase in Shh expression. Finally, we provide evidence that the fate of some of the Shh-expressing cells in the polarising region is to undergo apoptosis and contribute to the posterior necrotic zone during normal limb development. Taken together, these results show that there is a buffering system that regulates the number of Shh-expressing cells and thus polarising activity during limb development. They also suggest that cell death induced by Shh could be the cellular mechanism involved. Such an autoregulatory process based on cell death could represent a general way for regulating patterning signals in embryos.

dackel acts in the ectoderm of the zebrafish pectoral fin bud to maintain AER signaling

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4169-4178 ◽  
Author(s):  
H. Grandel ◽  
B.W. Draper ◽  
S. Schulte-Merker
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Induction Phase ◽  
Fibroblast Growth ◽  
Pectoral Fin ◽  
Vertebrate Limb ◽  
Fibroblast Growth Factor 10 ◽  
Vertebrate Limb Development

Classical embryological studies have implied the existence of an apical ectodermal maintenance factor (AEMF) that sustains signaling from the apical ectodermal ridge (AER) during vertebrate limb development. Recent evidence suggests that AEMF activity is composed of different signals involving both a sonic hedgehog (Shh) signal and a fibroblast growth factor 10 (Fgf10) signal from the mesenchyme. In this study we show that the product of the dackel (dak) gene is one of the components that acts in the epidermis of the zebrafish pectoral fin bud to maintain signaling from the apical fold, which is homologous to the AER of tetrapods. dak acts synergistically with Shh to induce fgf4 and fgf8 expression but independently of Shh in promoting apical fold morphogenesis. The failure of dak mutant fin buds to progress from the initial fin induction phase to the autonomous outgrowth phase causes loss of both AER and Shh activity, and subsequently results in a proximodistal truncation of the fin, similar to the result obtained by ridge ablation experiments in the chicken. Further analysis of the dak mutant phenotype indicates that the activity of the transcription factor engrailed 1 (En1) in the ventral non-ridge ectoderm also depends on a maintenance signal probably provided by the ridge. This result uncovers a new interaction between the AER and the dorsoventral organizer in the zebrafish pectoral fin bud.

scholarly journals Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development

1997 ◽  
Vol 62 (2) ◽  
pp. 175-182 ◽  
Author(s):  
Dirk Büscher ◽  
Birgit Bosse ◽  
Joachim Heymer ◽  
Ulrich Rüther
Keyword(s):  
Genetic Control ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Mouse Limb

scholarly journals Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

2015 ◽  
Vol 112 (16) ◽  
pp. 5075-5080 ◽  
Author(s):  
Ryutaro Akiyama ◽  
Hiroko Kawakami ◽  
Julia Wong ◽  
Isao Oishi ◽  
Ryuichi Nishinakamura ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Critical Role ◽  
Dependent Manner ◽  
Skeletal Element ◽  
Proximal Development ◽  
Limb Outgrowth ◽  
Common Regulator

Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.

scholarly journals Short- and long-range effects of Sonic hedgehog in limb development

2003 ◽  
Vol 100 (18) ◽  
pp. 10152-10157 ◽  
Author(s):  
R. Dillon ◽  
C. Gadgil ◽  
H. G. Othmer
Keyword(s):  
Long Range ◽  
Sonic Hedgehog ◽  
Limb Development

Role of dHAND in the anterior-posterior polarization of the limb bud: implications for the Sonic hedgehog pathway

Development ◽  
2000 ◽  
Vol 127 (10) ◽  
pp. 2133-2142 ◽  
Author(s):  
M. Fernandez-Teran ◽  
M.E. Piedra ◽  
I.S. Kathiriya ◽  
D. Srivastava ◽  
J.C. Rodriguez-Rey ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Limb Development ◽  
Mirror Image ◽  
Limb Bud ◽  
Bhlh Transcription Factor ◽  
Cardiovascular Development ◽  
Anterior Border ◽  
Lateral Plate ◽  
Shh Pathway ◽  
Anterior Posterior

dHAND is a basic helix-loop-helix (bHLH) transcription factor essential for cardiovascular development. Here we analyze its pattern of expression and functional role during chick limb development. dHAND expression was observed in the lateral plate mesoderm prior to emergence of the limb buds. Coincident with limb initiation, expression of dHAND became restricted to the posterior half of the limb bud. Experimental procedures that caused mirror-image duplications of the limb resulted in mirror-image duplications of the pattern of dHAND expression along the anterior-posterior axis. Retroviral overexpression of dHAND in the limb bud produced preaxial polydactyly, corresponding to mild polarizing activity at the anterior border. At the molecular level, misexpression of dHAND caused ectopic activation of members of the Sonic hedgehog (Shh) pathway, including Gli and Patched, in the anterior limb bud. A subset of infected embryos displayed ectopic anterior activation of Shh. Other factors implicated in anterior-posterior polarization of the bud such as the most 5′ Hoxd genes and Bmp2 were also ectopically activated at the anterior border. Our results indicate a role for dHAND in the establishment of anterior-posterior polarization of the limb bud.

scholarly journals Digit evolution in gymnophthalmid lizards

2015 ◽  
Author(s):  
Juliana Roscito ◽  
Pedro M. S. Nunes ◽  
Miguel T Rodrigues
Keyword(s):  
Sonic Hedgehog ◽  
Limb Development ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Molecular Signaling ◽  
Digit Number ◽  
Squamate Reptiles ◽  
Limb Reduction ◽  
Developmental Mechanisms ◽  
The Many

Background The tetrapod limb is a highly diverse structure, and reduction of the limbs accounts for much of the phenotypes observed within species. Squamate reptiles represent one of the many lineages in which the limbs have been greatly modified from the pentadactyl generalized pattern; within the group, limb-reduced morphologies can vary from minor reductions in size of elements to complete limblessness, with several intermediate forms in between. Even though limb reduction is widespread, it is not clear what are the evolutionary and developmental mechanisms involved in the formation of reduced limb morphologies. Methods In this study, we present an overview of limb morphology within the microteiid lizard group Gymnophthalmidae, focusing on digit number. Results We show that there are two major groups of limb-reduced gymnophthalmids. The first group is formed by lizard-like - and frequently pentadactyl - species, in which minor reductions (such as the loss of 1-2 phalanges mainly in digits I and V) are the rule; these morphologies generally correspond to those seen in other squamates. The second group is formed by species showing more drastic losses, which can include the absence of an externally distinct limb in adults. We also show the expression patterns of Sonic Hedgehog (Shh) in the greatly reduced fore and hindlimb of a serpentiform gymnophthalmid. Conclusions Our discussion focus on identifying shared patterns of limb reduction among tetrapods, and explaining these patterns and the morphological variation within the gymnophthalmids based on the current knowledge of the molecular signaling pathways that coordinate limb development.

scholarly journals A positional information gradient of sonic hedgehog is required for flight feather formation in avian wings

2019 ◽  
Author(s):  
Lara Busby ◽  
Cristina Aceituno ◽  
Caitlin McQueen ◽  
Constance A. Rich ◽  
Maria A. Ros ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Limb Development ◽  
Positional Information ◽  
Embryonic Chick ◽  
Flight Feather ◽  
Avian Flight ◽  
Theropod Dinosaurs ◽  
Wing Bud ◽  
Tissue Recombination ◽  
Recombination Experiments

Flight is a triumph of evolution that enabled the radiation and success of birds. A crucial step was the development of forelimb flight feathers that may have evolved for courtship or territorial displays in ancestral theropod dinosaurs. Classical tissue recombination experiments performed in the chick embryo provide evidence that signals operating during early limb development specify the position and identity of feathers. Here we show that a positional information gradient of Sonic hedgehog (Shh) signalling in the embryonic chick wing bud specifies the pattern of adult flight feathers in a defined spatial and temporal sequence that reflects their different identities. We reveal that the Shh signalling gradient is interpreted into specific patterns of flight feather-associated gene expression. Our data suggests that flight feather evolution involved the co-option of the pre-existing digit patterning mechanism and therefore uncovers an embryonic process that played a fundamental step in the evolution of avian flight.

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