TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human
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Evaluation Summary:
In this study, the authors used a chick and a mouse model and human tissues to analyze the role of the conserved protein TALPID3/KIAA0586, previously linked to ciliogenesis, in gut development. Using a multi-species approach, the authors conclude that TALPID3 has an evolutionary conserved role in regulating gut patterning along the radial axis, apparently orchestrated by neural crest cells in a non-cell-autonomous manner and mediated by perturbation of Sonic Hedgehog signaling and the composition of extracellular matrix.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript.The reviewers remained anonymous to the authors.)
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Abstract
TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning.
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Evaluation Summary:
In this study, the authors used a chick and a mouse model and human tissues to analyze the role of the conserved protein TALPID3/KIAA0586, previously linked to ciliogenesis, in gut development. Using a multi-species approach, the authors conclude that TALPID3 has an evolutionary conserved role in regulating gut patterning along the radial axis, apparently orchestrated by neural crest cells in a non-cell-autonomous manner and mediated by perturbation of Sonic Hedgehog signaling and the composition of extracellular matrix.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript.The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
TALPID3/KIAA0586 is an evolutionary conserved protein which plays a critical TALPID3/KIAA0586 role in ciliogenesis that have been shown to be essential for correct vertebrate development. In this study, the authors investigate the impact of TALPID3 mutation in developing gastrointestinal tract in chicken and humans and demonstrated that smooth muscle was mispatterned, and enteric nervous system (ENS) cells were mislocalized. Focusing on ENS, chicken grafting and conditional mouse experiments demonstrated that smooth muscle alteration could not be rescued by TALPID3 expression in ENS cells. Conversely, using reverse chicken grafting, the authors demonstrated that disruption of TALPID3 in the ENS is sufficient to conduct to smooth muscle and epithelium alteration. Moreover, they observed defective expression …
Reviewer #1 (Public Review):
TALPID3/KIAA0586 is an evolutionary conserved protein which plays a critical TALPID3/KIAA0586 role in ciliogenesis that have been shown to be essential for correct vertebrate development. In this study, the authors investigate the impact of TALPID3 mutation in developing gastrointestinal tract in chicken and humans and demonstrated that smooth muscle was mispatterned, and enteric nervous system (ENS) cells were mislocalized. Focusing on ENS, chicken grafting and conditional mouse experiments demonstrated that smooth muscle alteration could not be rescued by TALPID3 expression in ENS cells. Conversely, using reverse chicken grafting, the authors demonstrated that disruption of TALPID3 in the ENS is sufficient to conduct to smooth muscle and epithelium alteration. Moreover, they observed defective expression of extracellular matrix (ECM) components (CSS56 and COL9) in the mesenchyme of chick TALPID3 mutant suggesting that both smooth muscle and ECM alteration participated to ENS mispatterning.
TALPID3 mutant gastrointestinal phenotype harbors close similarity to those observed in sonic hedgehog mutant mice, moreover TALPID3 has been shown to regulate the phosphorylation of GLI2 and GLI3 that act as transcriptional effectors to control downstream Hedgehog target genes. To evaluate misregulation of Hedgehog pathway in TALPID3 mutant, they authors investigate the expression of Patched receptor that bind Hedgehog ligands and observed in chicken and Humans reduced expression of PTCH, suggesting an inhibition of the Hedgehog signaling pathway.
In summary, the authors showed that TALPID3 plays role in neuronal-mesenchymal-epithelial interactions necessary for normal gastrointestinal tract development in Vertebrates.
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Reviewer #2 (Public Review):
In this study, Delalande et al. used two different animal models (chick and mouse) and human tissues to analyze the role of TALPID3/KIAA0586 in gut development. The main strength of this work is the multi-species approach. Capitalizing on this multi-species approach, the authors conclude that TALPID3 has an evolutionary-conserved role in regulating gut patterning along the radial axis, apparently orchestrated by neural crest cells in a non-cell-autonomous manner and mediated by perturbation of SHH signaling/ECM composition. Unfortunately, these attractive conclusions are not convincingly supported by the results. Data (over)interpretation is a major weakness here. There is also a lack of consistency in the developmental stages that were studied and the choice of markers that were used. In the end, despite …
Reviewer #2 (Public Review):
In this study, Delalande et al. used two different animal models (chick and mouse) and human tissues to analyze the role of TALPID3/KIAA0586 in gut development. The main strength of this work is the multi-species approach. Capitalizing on this multi-species approach, the authors conclude that TALPID3 has an evolutionary-conserved role in regulating gut patterning along the radial axis, apparently orchestrated by neural crest cells in a non-cell-autonomous manner and mediated by perturbation of SHH signaling/ECM composition. Unfortunately, these attractive conclusions are not convincingly supported by the results. Data (over)interpretation is a major weakness here. There is also a lack of consistency in the developmental stages that were studied and the choice of markers that were used. In the end, despite some interesting observations, this study looks incomplete in its current form.
While the conclusions are attractive, they are not convincingly supported by the results. Data (over)interpretation is a major weakness here. There is also a lack of consistency in the developmental stages that were studied and the choice of markers that were used. In the end, despite some interesting observations, this study looks incomplete in its current form.
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