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 Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Irene Delgado ◽  
Giovanna Giovinazzo ◽  
Susana Temiño ◽  
Yves Gauthier ◽  
Aurelio Balsalobre ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Limb Development ◽  
Critical Factor ◽  
Interaction Networks ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Hox Proteins ◽  
Mouse Limb ◽  
Limb Initiation

AbstractMeis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1/2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis.

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.

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.

The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor

Development ◽  
1997 ◽  
Vol 124 (11) ◽  
pp. 2235-2244 ◽  
Author(s):  
H. Ohuchi ◽  
T. Nakagawa ◽  
A. Yamamoto ◽  
A. Araga ◽  
T. Ohata ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Limb Bud ◽  
Fibroblast Growth ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Bud Formation ◽  
Limb Mesenchyme ◽  
Vertebrate Limb ◽  
Fgf10 Expression ◽  
Zone Of Polarizing Activity

Vertebrate limb formation has been known to be initiated by a factor(s) secreted from the lateral plate mesoderm. In this report, we provide evidence that a member of the fibroblast growth factor (FGF) family, FGF10, emanates from the prospective limb mesoderm to serve as an endogenous initiator for limb bud formation. Fgf10 expression in the prospective limb mesenchyme precedes Fgf8 expression in the nascent apical ectoderm. Ectopic application of FGF10 to the chick embryonic flank can induce Fgf8 expression in the adjacent ectoderm, resulting in the formation of an additional complete limb. Expression of Fgf10 persists in the mesenchyme of the established limb bud and appears to interact with Fgf8 in the apical ectoderm and Sonic hedgehog in the zone of polarizing activity. These results suggest that FGF10 is a key mesenchymal factor involved in the initial budding as well as the continuous outgrowth of vertebrate limbs.

scholarly journals 09-P001 Role of Flrt3 during vertebrate limb development

2009 ◽  
Vol 126 ◽  
pp. S151
Author(s):  
Ana Raquel Tomás ◽  
Joaquín Rodríguez León
Keyword(s):  
Limb Development ◽  
Vertebrate Limb ◽  
Vertebrate Limb Development

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.

scholarly journals Essential roles of zebrafish bmp2a, fgf10, and fgf24 in the specification of the ventral pancreas

2012 ◽  
Vol 23 (5) ◽  
pp. 945-954 ◽  
Author(s):  
François Naye ◽  
Marianne L. Voz ◽  
Nathalie Detry ◽  
Matthias Hammerschmidt ◽  
Bernard Peers ◽  
...  
Keyword(s):  
Fibroblast Growth ◽  
Lateral Plate Mesoderm ◽  
Loss Of Function ◽  
Lateral Plate ◽  
Bmp Pathway ◽  
Ventral Pancreas ◽  
Pancreas Agenesis ◽  
Gut Endoderm ◽  
Hepatic Markers

In vertebrates, pancreas and liver arise from bipotential progenitors located in the embryonic gut endoderm. Bone morphogenic protein (BMP) and fibroblast growth factor (FGF) signaling pathways have been shown to induce hepatic specification while repressing pancreatic fate. Here we show that BMP and FGF factors also play crucial function, at slightly later stages, in the specification of the ventral pancreas. By analyzing the pancreatic markers pdx1, ptf1a, and hlxb9la in different zebrafish models of BMP loss of function, we demonstrate that the BMP pathway is required between 20 and 24 h postfertilization to specify the ventral pancreatic bud. Knockdown experiments show that bmp2a, expressed in the lateral plate mesoderm at these stages, is essential for ventral pancreas specification. Bmp2a action is not restricted to the pancreatic domain and is also required for the proper expression of hepatic markers. By contrast, through the analysis of fgf10−/−; fgf24−/− embryos, we reveal the specific role of these two FGF ligands in the induction of the ventral pancreas and in the repression of the hepatic fate. These mutants display ventral pancreas agenesis and ectopic masses of hepatocytes. Overall, these data highlight the dynamic role of BMP and FGF in the patterning of the hepatopancreatic region.

Control of digit formation by activin signalling

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2161-2170 ◽  
Author(s):  
R. Merino ◽  
D. Macias ◽  
Y. Ganan ◽  
J. Rodriguez-Leon ◽  
A.N. Economides ◽  
...  
Keyword(s):  
Gene Expression ◽  
Limb Development ◽  
Local Administration ◽  
Exogenous Application ◽  
Signalling Molecules ◽  
Close Interaction ◽  
Vertebrate Limb ◽  
Vertebrate Limb Development ◽  
Bmp Signalling

Major advances in the genetics of vertebrate limb development have been obtained in recent years. However, the nature of the signals which trigger differentiation of the mesoderm to form the limb skeleton remains elusive. Previously, we have obtained evidence for a role of TGFbeta2 in digit formation. Here, we show that activins A and B and/or AB are also signals involved in digit skeletogenesis. activin betaA gene expression correlates with the initiation of digit chondrogenesis while activin betaB is expressed coincidently with the formation of the last phalanx of each digit. Exogenous administration of activins A, B or AB into the interdigital regions induces the formation of extra digits. follistatin, a natural antagonist of activins, is expressed, under the control of activin, peripherally to the digit chondrogenic aggregates marking the prospective tendinous blastemas. Exogenous application of follistatin blocks physiological and activin-induced digit formation. Evidence for a close interaction between activins and other signalling molecules, such as BMPs and FGFs, operating at the distal tip of the limb at these stages is also provided. Chondrogenesis by activins is mediated by BMPs through the regulation of the BMP receptor bmpR-1b and in turn activin expression is upregulated by BMP signalling. In addition, AER hyperactivity secondary to Wnt3A misexpression or local administration of FGFs, inhibits activin expression. In correlation with the restricted expression of activins in the course of digit formation, neither activin nor follistatin treatment affects the development of the skeletal components of the stylopod or zeugopod indicating that the formation of the limb skeleton is regulated by segment-specific chondrogenic signals.

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