The incomplete inactivation of <i>Fgf8</i> in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP‐mediated cell death

Delgado, Irene; Domínguez-Frutos, Elena; Schimmang, Thomas; Ros, María A.

doi:10.1002/dvdy.21452

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…We find that the change in patterning in the mutants is correlated with asymmetrical cell death of the distal marginal fin fold as well as a reduction of shh expression. This finding is similar to the effect of loss of AER function resulting in anterior-distal cell death and reduction of Shh activity in tetrapod limbs [37]–[39]. While there has not been any previous indication of a role of Eda signaling in tetrapod limb development, both the expression of Edar and related receptor, Troy , have been detected in the AER of mice [40],[41].…”

Section: Discussionsupporting

confidence: 77%

Zebrafish eda and edar Mutants Reveal Conserved and Ancestral Roles of Ectodysplasin Signaling in Vertebrates

et al. 2008

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The genetic basis of the development and variation of adult form of vertebrates is not well understood. To address this problem, we performed a mutant screen to identify genes essential for the formation of adult skeletal structures of the zebrafish. Here, we describe the phenotypic and molecular characterization of a set of mutants showing loss of adult structures of the dermal skeleton, such as the rays of the fins and the scales, as well as the pharyngeal teeth. The mutations represent adult-viable, loss of function alleles in the ectodysplasin (eda) and ectodysplasin receptor (edar) genes. These genes are frequently mutated in the human hereditary disease hypohidrotic ectodermal dysplasia (HED; OMIM 224900, 305100) that affects the development of integumentary appendages such as hair and teeth. We find mutations in zebrafish edar that affect similar residues as mutated in human cases of HED and show similar phenotypic consequences. eda and edar are not required for early zebrafish development, but are rather specific for the development of adult skeletal and dental structures. We find that the defects of the fins and scales are due to the role of Eda signaling in organizing epidermal cells into discrete signaling centers of the scale epidermal placode and fin fold. Our genetic analysis demonstrates dose-sensitive and organ-specific response to alteration in levels of Eda signaling. In addition, we show substantial buffering of the effect of loss of edar function in different genetic backgrounds, suggesting canalization of this developmental system. We uncover a previously unknown role of Eda signaling in teleosts and show conservation of the developmental mechanisms involved in the formation and variation of both integumentary appendages and limbs. Lastly, our findings point to the utility of adult genetic screens in the zebrafish in identifying essential developmental processes involved in human disease and in morphological evolution.

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Section: Discussionsupporting

confidence: 77%

Zebrafish eda and edar Mutants Reveal Conserved and Ancestral Roles of Ectodysplasin Signaling in Vertebrates

et al. 2008

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“…To circumvent these issues and avoid the neural phenotype from Sp8 null mutants, we used an Sp8 floxed conditional allele ( Sp8 f ; [36]) to remove it specifically from the limb ectoderm. Among the available lines with Cre activity in the limb ectoderm ( Msx2Cre [37]; Brn4Cre [17]; RARCre [38]; AP2αCre [39]; Mox2Cre [40]), we selected the AP2αCre line because it has been reported to drive very early Cre function in both fore and hindlimbs, at least before activation of Fgf8 [41]. Because Sp8 is already expressed at E7.5 in the embryonic ectoderm ([24], [25] and authors' personal observations), we decided to determine in more detail the activity of the AP2α;Cre transgenic line using the ROSA26 reporter strain (R26R; [42]).…”

Section: Resultsmentioning

confidence: 99%

Sp6 and Sp8 Transcription Factors Control AER Formation and Dorsal-Ventral Patterning in Limb Development

et al. 2014

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The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. The induction of the AER is a complex process that relies on integrated interactions among the Fgf, Wnt, and Bmp signaling pathways that operate within the ectoderm and between the ectoderm and the mesoderm of the early limb bud. The transcription factors Sp6 and Sp8 are expressed in the limb ectoderm and AER during limb development. Sp6 mutant mice display a mild syndactyly phenotype while Sp8 mutants exhibit severe limb truncations. Both mutants show defects in AER maturation and in dorsal-ventral patterning. To gain further insights into the role Sp6 and Sp8 play in limb development, we have produced mice lacking both Sp6 and Sp8 activity in the limb ectoderm. Remarkably, the elimination or significant reduction in Sp6;Sp8 gene dosage leads to tetra-amelia; initial budding occurs, but neither Fgf8 nor En1 are activated. Mutants bearing a single functional allele of Sp8 (Sp6−/−;Sp8+/−) exhibit a split-hand/foot malformation phenotype with double dorsal digit tips probably due to an irregular and immature AER that is not maintained in the center of the bud and on the abnormal expansion of Wnt7a expression to the ventral ectoderm. Our data are compatible with Sp6 and Sp8 working together and in a dose-dependent manner as indispensable mediators of Wnt/βcatenin and Bmp signaling in the limb ectoderm. We suggest that the function of these factors links proximal-distal and dorsal-ventral patterning.

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“…Interdigital PCD in developing limb is tightly controlled under the effects of different signaling factors like fibroblast growth factors (FGFs) (Delgado et al, 2008; Montero et al, 2001; Pajni-Underwood et al, 2007; Salas-Vidal et al, 2001), BMPs (Ganan et al, 1996; Guha et al, 2002; Macias et al, 1997; Pajni-Underwood et al, 2007; Salas-Vidal et al, 2001; Zou and Niswander, 1996), transforming growth factor-beta (TGF-β) (Ganan et al, 1996), Msx-2 (Marazzi et al, 1997; Salas-Vidal et al, 2001), Wnts (Grotewold and Ruther, 2002), Shh (Buscher et al, 1997) and retinoic acid (Ali-Khan and Hales, 2006; Galdones et al, 2006). BMP signaling in the AER has been shown to regulate interdigital PCD but the identity of the intracellular mediator remains unclear (Maatouk et al, 2009; Pajni-Underwood et al, 2007; Zuzarte-Luis and Hurle, 2005).…”

Section: Introductionmentioning

confidence: 99%

Smad1/Smad5 signaling in limb ectoderm functions redundantly and is required for interdigital programmed cell death

Wong

Behringer²,

Kwan

2012

Developmental Biology

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Bone morphogenetic proteins (BMPs) are secreted signals that regulate apical ectodermal ridge (AER) functions and interdigital programmed cell death (PCD) of developing limb. However the identities of the intracellular mediators of these signals are unknown. To investigate the role of Smad proteins in BMP-regulated AER functions in limb development, we inactivated Smad1 and Smad5 selectively in AER and ventral ectoderm of developing limb, using Smad1 or/and Smad5 floxed alleles and an En1Cre/+ knock-in allele. Single inactivation of either Smad1 or Smad5 did not result in limb abnormalities. However, the Smad1/Smad5 double mutants exhibited syndactyly due to a reduction in interdigital PCD and an increase in interdigital cell proliferation. Cell tracing experiments in the Smad1/Smad5 double mutants showed that ventral ectoderm became thicker and the descendents of ventral En1Cre/+ expressing ectodermal cells were located at dorsal interdigital regions. At the molecular level, Fgf8 expression was prolonged in the interdigital ectoderm of embryonic day (E) 13 Smad1/Smad5 double mutants, suggesting that the ectopic Fgf8 expression may serve as a survival signal for interdigital epithelial and mesenchymal cells. Our result suggests that Smad1 and Smad5 are required and function redundantly as intracellular mediators for BMP signaling in the AER and ventral ectoderm. Smad1/Smad5 signaling in the AER and ventral ectoderm regulates interdigital tissue regression of developing limb. Our mutants with defects in interdigital PCD could also serve as a valuable model for investigation of PCD regulation machinery.

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The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP‐mediated cell death

Cited by 12 publications

References 44 publications

Zebrafish eda and edar Mutants Reveal Conserved and Ancestral Roles of Ectodysplasin Signaling in Vertebrates

Zebrafish eda and edar Mutants Reveal Conserved and Ancestral Roles of Ectodysplasin Signaling in Vertebrates

Sp6 and Sp8 Transcription Factors Control AER Formation and Dorsal-Ventral Patterning in Limb Development

Smad1/Smad5 signaling in limb ectoderm functions redundantly and is required for interdigital programmed cell death

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