The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10

Development ◽  
2002 ◽  
Vol 129 (22) ◽  
pp. 5161-5170 ◽  
Author(s):  
Jennifer K. Ng ◽  
Yasuhiko Kawakami ◽  
Dirk Büscher ◽  
Ángel Raya ◽  
Tohru Itoh ◽  
...  
Keyword(s):  
Limb Development ◽  
Gene Families ◽  
Chick Embryos ◽  
Loss Of Function ◽  
T Box ◽  
Vertebrate Limb ◽  
Limb Outgrowth ◽  
Tbx5 Expression ◽  
Necessary And Sufficient ◽  
Limb Initiation

A major gap in our knowledge of development is how the growth and identity of tissues and organs are linked during embryogenesis. The vertebrate limb is one of the best models to study these processes. Combining mutant analyses with gain- and loss-of-function approaches in zebrafish and chick embryos, we show that Tbx5, in addition to its role governing forelimb identity,is both necessary and sufficient for limb outgrowth. We find thatTbx5 functions downstream of WNT signaling to regulateFgf10, which, in turn, maintains Tbx5 expression during limb outgrowth. Furthermore, our results indicate that Tbx5 andWnt2b function together to initiate and specify forelimb outgrowth and identity. The molecular interactions governed by members of the T-box,Wnt and Fgf gene families uncovered in this study provide a framework for understanding not only limb development, but how outgrowth and identity of other tissues and organs of the embryo may be regulated.

The dominant hemimelia mutation uncouples epithelial-mesenchymal interactions and disrupts anterior mesenchyme formation in mouse hindlimbs

Development ◽  
1999 ◽  
Vol 126 (21) ◽  
pp. 4729-4736
Author(s):  
L. Lettice ◽  
J. Hecksher-Sorensen ◽  
R.E. Hill
Keyword(s):  
Gene Expression ◽  
Pattern Formation ◽  
Limb Development ◽  
Limb Bud ◽  
Mouse Mutation ◽  
Number Of Factors ◽  
Limb Outgrowth ◽  
Gene Functions ◽  
Regulatory Loop ◽  
Limb Initiation

Epithelial-mesenchymal interactions are essential for both limb outgrowth and pattern formation in the limb. Molecules capable of communication between these two tissues are known and include the signaling molecules SHH and FGF4, FGF8 and FGF10. Evidence suggests that the pattern and maintenance of expression of these genes are dependent on a number of factors including regulatory loops between genes expressed in the AER and those in the underlying mesenchyme. We show here that the mouse mutation dominant hemimelia (Dh) alters the pattern of gene expression in the AER such that Fgf4, which is normally expressed in a posterior domain, and Fgf8, which is expressed throughout are expressed in anterior patterns. We show that maintenance of Shh expression in the posterior mesenchyme is not dependent on either expression of Fgf4 or normal levels of Fgf8 in the overlying AER. Conversely, AER expression of Fgf4 is not directly dependent on Shh expression. Also the reciprocal regulatory loop proposed for Fgf8 in the AER and Fgf10 in the underlying mesenchyme is also uncoupled by this mutation. Early during the process of limb initiation, Dh is involved in regulating the width of the limb bud, the mutation resulting in selective loss of anterior mesenchyme. The Dh gene functions in the initial stages of limb development and we suggest that these initial roles are linked to mechanisms that pattern gene expression in the AER.

The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development

Development ◽  
1998 ◽  
Vol 125 (22) ◽  
pp. 4417-4425 ◽  
Author(s):  
M. Takahashi ◽  
K. Tamura ◽  
D. Buscher ◽  
H. Masuya ◽  
S. Yonei-Tamura ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Limb Development ◽  
Feedback Loop ◽  
Limb Bud ◽  
Negative Regulator ◽  
Negative Feedback Loop ◽  
Vertebrate Limb ◽  
Limb Outgrowth ◽  
Vertebrate Limb Development

We have determined that Strong's Luxoid (lstJ) [corrected] mice have a 16 bp deletion in the homeobox region of the Alx-4 gene. This deletion, which leads to a frame shift and a truncation of the Alx-4 protein, could cause the polydactyly phenotype observed in lstJ [corrected] mice. We have cloned the chick homologue of Alx-4 and investigated its expression during limb outgrowth. Chick Alx-4 displays an expression pattern complementary to that of shh, a mediator of polarizing activity in the limb bud. Local application of Sonic hedgehog (Shh) and Fibroblast Growth Factor (FGF), in addition to ectodermal apical ridge removal experiments suggest the existence of a negative feedback loop between Alx-4 and Shh during limb outgrowth. Analysis of polydactylous mutants indicate that the interaction between Alx-4 and Shh is independent of Gli3, a negative regulator of Shh in the limb. Our data suggest the existence of a negative feedback loop between Alx-4 and Shh during vertebrate limb outgrowth.

Lhx2, a vertebrate homologue of apterous, regulates vertebrate limb outgrowth

Development ◽  
1998 ◽  
Vol 125 (20) ◽  
pp. 3925-3934 ◽  
Author(s):  
C. Rodriguez-Esteban ◽  
J.W. Schwabe ◽  
J.D. Pena ◽  
D.E. Rincon-Limas ◽  
J. Magallon ◽  
...  
Keyword(s):  
Cell Fate ◽  
Wing Development ◽  
Dorsoventral Axis ◽  
Drosophila Wing ◽  
Vertebrate Limb ◽  
Limb Outgrowth ◽  
Necessary And Sufficient ◽  
Dorsal Cell Fate

apterous specifies dorsal cell fate and directs outgrowth of the wing during Drosophila wing development. Here we show that, in vertebrates, these functions appear to be performed by two separate proteins. Lmx-1 is necessary and sufficient to specify dorsal identity and Lhx2 regulates limb outgrowth. Our results suggest that Lhx2 is closer to apterous than Lmx-1, yet, in vertebrates, Lhx2 does not specify dorsal cell fate. This implies that in vertebrates, unlike Drosophila, limb outgrowth can be dissociated from the establishment of the dorsoventral axis.

scholarly journals Reciprocal Mouse and Human Limb Phenotypes Caused by Gain- and Loss-of-Function Mutations Affecting Lmbr1

Genetics ◽  
2001 ◽  
Vol 159 (2) ◽  
pp. 715-726
Author(s):  
Richard M Clark ◽  
Paul C Marker ◽  
Erich Roessler ◽  
Amalia Dutra ◽  
John C Schimenti ◽  
...  
Keyword(s):  
Limb Development ◽  
Chromosomal Region ◽  
Loss Of Function ◽  
Digit Number ◽  
Limb Defects ◽  
Major Locus ◽  
Preaxial Polydactyly ◽  
Vertebrate Limb ◽  
In Trans ◽  
Human Limb

Abstract The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb.

scholarly journals Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes

Development ◽  
2000 ◽  
Vol 127 (18) ◽  
pp. 3961-3970 ◽  
Author(s):  
N. Mercader ◽  
E. Leonardo ◽  
M.E. Piedra ◽  
C. Martinez-A ◽  
M.A. Ros ◽  
...  
Keyword(s):  
Limb Development ◽  
Fibroblast Growth ◽  
Specific Function ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Vertebrate Limb ◽  
Proximal Determinant ◽  
Vertebrate Limb Development ◽  
Limb Initiation

Vertebrate limbs develop in a temporal proximodistal sequence, with proximal regions specified and generated earlier than distal ones. Whereas considerable information is available on the mechanisms promoting limb growth, those involved in determining the proximodistal identity of limb parts remain largely unknown. We show here that retinoic acid (RA) is an upstream activator of the proximal determinant genes Meis1 and Meis2. RA promotes proximalization of limb cells and endogenous RA signaling is required to maintain the proximal Meis domain in the limb. RA synthesis and signaling range, which initially span the entire lateral plate mesoderm, become restricted to proximal limb domains by the apical ectodermal ridge (AER) activity following limb initiation. We identify fibroblast growth factor (FGF) as the main molecule responsible for this AER activity and propose a model integrating the role of FGF in limb cell proliferation, with a specific function in promoting distalization through inhibition of RA production and signaling.

scholarly journals Involvement of FGF-8 in initiation, outgrowth and patterning of the vertebrate limb

Development ◽  
1996 ◽  
Vol 122 (6) ◽  
pp. 1737-1750 ◽  
Author(s):  
A. Vogel ◽  
C. Rodriguez ◽  
J.C. Izpisua-Belmonte
Keyword(s):  
Limb Development ◽  
Growth Control ◽  
Fibroblast Growth Factors ◽  
Apical Ectodermal Ridge ◽  
Young Chick ◽  
Expression Studies ◽  
Vertebrate Limb ◽  
Vertebrate Limb Development ◽  
Ridge Structures ◽  
Limb Initiation

Fibroblast Growth Factors (FGFs) are signaling molecules that are important in patterning and growth control during vertebrate limb development. Beads soaked in FGF-1, FGF-2 and FGF-4 are able to induce additional limbs when applied to the flank of young chick embryos (Cohn, M.J., Izpisua-Belmonte, J-C., Abud, H., Heath, J. K., Tickle, C. (1995) Cell 80, 739–746). However, biochemical and expression studies suggest that none of these FGFs is the endogenous signal that initiates limb development. During chick limb development, Fgf-8 transcripts are detected in the intermediate mesoderm and subsequently in the prelimb field ectoderm prior to the formation of the apical ectodermal ridge, structures required for limb initiation and outgrowth, respectively. Later on, Fgf-8 expression is restricted to the ridge cells and expression disappears when the ridge regresses. Application of FGF-8 protein to the flank induces the development of additional limbs. Moreover, we show that FGF-8 can replace the apical ectodermal ridge to maintain Shh expression and outgrowth and patterning of the developing chick limb. Furthermore, continuous and widespread misexpression of FGF-8 causes limb truncations and skeletal alterations with phocomelic or achondroplasia phenotype. Thus, FGF-8 appears to be a key signal involved in initiation, outgrowth and patterning of the developing vertebrate limb.

Learning about Vertebrate Limb Development

2014 ◽  
Vol 76 (7) ◽  
pp. 471-475 ◽  
Author(s):  
Jennifer O. Liang ◽  
Matthew Noll ◽  
Shayna Olsen
Keyword(s):  
Limb Development ◽  
Model System ◽  
Chick Embryos ◽  
Laboratory Exercise ◽  
Vertebrate Limb ◽  
Teachers And Students ◽  
Undergraduate Laboratory ◽  
Vertebrate Limb Development ◽  
History Of ◽  
Upper Level

We have developed an upper-level undergraduate laboratory exercise that enables students to replicate a key experiment in developmental biology. In this exercise, students have the opportunity to observe live chick embryos and stain the apical ectodermal ridge, a key tissue required for development of the vertebrate limb. Impressively, every student who has tried this protocol has been successful, making it a good introduction to the use of the chick model system in studying development. The array of materials about limb development, using chick embryos in teaching laboratories, and the history of this experiment provide a rich background for teachers and students.

Genetic and developmental bases of serial homology in vertebrate limb evolution

Development ◽  
2000 ◽  
Vol 127 (24) ◽  
pp. 5233-5244 ◽  
Author(s):  
I. Ruvinsky ◽  
J.J. Gibson-Brown
Keyword(s):  
Limb Development ◽  
Molecular Mechanisms ◽  
Hox Genes ◽  
Single Gene ◽  
Genetic Data ◽  
Gene Families ◽  
The Body ◽  
Morphological Description ◽  
Developmental Systems ◽  
Vertebrate Limb

Two sets of paired appendages are a characteristic feature of the body plan of jawed vertebrates. While the fossil record provides a good morphological description of limb evolution, the molecular mechanisms involved in this process are only now beginning to be understood. It is likely that the genes essential for limb development in modern vertebrates were also important players during limb evolution. In recent years, genes from a number of gene families have been described that play important roles both in limb induction and in later patterning processes. These advances facilitate inquiries into several important aspects of limb evolution such as their origin, position along the body axis, number and identity. Integrating paleontological, developmental and genetic data, we propose models to explain the evolution of paired appendages in vertebrates. Whereas previous syntheses have tended to focus on the roles of genes from a single gene family, most notably Hox genes, we emphasize the importance of considering the interactions among multiple genes from different gene families for understanding the evolution of complex developmental systems. Our models, which underscore the roles of gene duplication and regulatory ‘tinkering’, provide a conceptual framework for elucidating the evolution of serially homologous structures in general, and thus contribute to the burgeoning field seeking to uncover the genetic and developmental bases of evolution.

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