<i>Vangl</i>facilitates mesenchymal thinning during lung sacculation independently of<i>Celsr</i>

Paramore, Sarah V.; Trenado-Yuste, Carolina; Sharan, Rishabh; Devenport, Danelle; Nelson, Celeste M.

doi:10.1101/2022.12.28.522148

Cited by 3 publications

(2 citation statements)

References 74 publications

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“…2A). Further, we found that removal of Vangl1/2 in the epiCKO animals leads to a loss of Celsr1 polarization in the trachea (Paramore et al, 2022); thus, using the ShhCre driver to delete Vangl1/2 causes loss of a functional PCP complex in the embryonic lung epithelium.…”

Section: Vangl2-mutant Lungs Have a Reduction In Airway Epithelial Vo...mentioning

confidence: 78%

MesenchymalVanglfacilitates airway elongation and widening independently of the planar cell polarity complex

Paramore¹,

Goodwin²,

Devenport³

et al. 2023

Preprint

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A hallmark of mammalian lungs is the fractal nature of the bronchial tree. In the adult, each successive generation of airways is a fraction of the size of the parental branch. This fractal structure is physiologically beneficial, as it minimizes the energy needed for breathing. Achieving this pattern likely requires precise control of airway length and diameter, as the branches of the embryonic airways initially lack the fractal scaling observed in those of the adult lung. In epithelial monolayers and tubes, directional growth can be regulated by the planar cell polarity (PCP) complex. Here, we comprehensively characterized the roles of PCP-complex components in airway initiation, elongation, and widening during branching morphogenesis of the murine lung. Using tissue-specific knockout mice, we surprisingly found that branching morphogenesis proceeds independently of PCP-component expression in the developing airway epithelium. Instead, we found a novel, Celsr1-independent role for the PCP component Vangl in the pulmonary mesenchyme. Specifically, mesenchymal loss of Vangl1/2 leads to defects in branch initiation, elongation, and widening. At the cellular level, we observe changes in the shape of smooth muscle cells that indicate a potential defect in collective mesenchymal rearrangements, which we hypothesize are necessary for lung morphogenesis. Our data thus reveal an explicit function for Vangl that is independent of the core PCP complex, suggesting a functional diversification of PCP components in vertebrate development. These data also reveal an essential role for the embryonic mesenchyme in generating the fractal structure of airways of the mature lung.

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Section: Vangl2-mutant Lungs Have a Reduction In Airway Epithelial Vo...mentioning

confidence: 78%

MesenchymalVanglfacilitates airway elongation and widening independently of the planar cell polarity complex

Paramore¹,

Goodwin²,

Devenport³

et al. 2023

Preprint

Self Cite

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“…Loss of Rab11a/b in the pancreas leads to highly disorganized epithelial defects due to the mis-localization of apical-basal proteins laminin, Par3, and aPKC, but this study did not examine whether this was due to Vangl mis-localization 37 . Interestingly, Vangl2 has a PCP-independent role in the developing lung mesenchyme during branching morphogenesis 38,39 . Neither the looptail mutation nor conditional knockout of Vangl2 using ShhCre impairs trachea-esophageal separation, however, a different Cre driver with earlier recombination in the foregut might lead to separation anomalies.…”

Section: Discussionmentioning

confidence: 99%

Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

Edwards,

Kashyap,

Warren

et al. 2023

Preprint

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The developmental basis of esophageal atresia and tracheoesophageal fistulas (EA/TEF), life-threatening congenital anomalies where the embryonic foregut fails to properly separate into trachea and esophagus, is poorly understood. Recent genome sequencing reveals that de novo variants in intracellular trafficking genes are enriched in EA/TEF patients, suggesting that these cellular processes regulate foregut morphogenesis. Here we show that mutation of orthologous genes in Xenopus disrupts trachea-esophageal separation like EA/TEF patients. We identify the underlying mechanism showing that the Rab11a recycling endosome pathway is required to localize Vangl-Celsr polarity complexes at the apical cell surface where opposite sides of the foregut tube fuses forming a transient epithelial bilayer. A partial loss of endosome trafficking or knockdown of the Vangl/Celsr complex disrupts cell polarity and planar cell division. Mutant cells accumulate in the disorganize septum, fail to downregulate cadherin, and do not separate into distinct trachea and esophagus. These data provide new insights into the mechanisms of congenital anomalies and general paradigms of tissue fusion during organogenesis.

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A quick guide to (transmembrane) planar cell polarity mouse strains

Paramore

2023

Nat Rev Mol Cell Biol

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Vanglfacilitates mesenchymal thinning during lung sacculation independently ofCelsr

Cited by 3 publications

References 74 publications

MesenchymalVanglfacilitates airway elongation and widening independently of the planar cell polarity complex

MesenchymalVanglfacilitates airway elongation and widening independently of the planar cell polarity complex

Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

A quick guide to (transmembrane) planar cell polarity mouse strains

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