Van Gogh-like 2 is essential for the architectural patterning of the mammalian biliary tree
Notice bibliographique
Résumé
•Bile ducts express high levels of Planar Cell Polarity genes when they are undergoing morphogenesis.•VANGL2 physically interacts with Desmosome protein DSG1A and patterns cell-cell contacts.•Loss of functional VANGL2 prevents ducts from coordinating their actin cytoskeleton normally.•Ducts with dysregulated cytoskeletal dynamics from dysfunctional VANGL2 fail to connect and form a continuous biliary tree. Background & AimsIn the developing liver, bipotent epithelial progenitor cells known as hepatoblasts undergo lineage segregation to form the two major epithelial cell types, hepatocytes that constitute the bulk of the liver parenchyma and biliary epithelial cells (cholangiocytes) which comprise the bile duct, a complex tubular network which is critical for normal liver function. Notch and TGFβ signalling promote the formation of a sheet of biliary epithelial cells, the ductal plate that organises into discontinuous tubular structures. How these structures elongate and connect to form a continuous duct remains undefined. We aimed to define the mechanisms by which the ductal plate transitions from simple sheet of epithelial cells to a complex and connected bile duct.MethodsBy combining single cell RNA sequencing from embryonic mouse livers with genetic tools and organoid models we functionally dissected the role of planar cell polarity in duct patterning.ResultsWe show that the planar cell polarity protein, VANGL2 is expressed late in intrahepatic bile duct development and patterns the formation of cell-cell contacts between biliary cells. The patterning of these cell contacts regulates the normal polarisation of the actin cytoskeleton within biliary cells and loss of Vangl2-function results in the abnormal distribution of cortical actin remodelling resulting in the failure of bile duct formation.ConclusionsPlanar cell polarity is a critical step in the post-specification sculpture of the bile duct and is essential for establishing normal tissue architecture.Impact and ImplicationsHuman disease and mouse models have allowed us to define how the mammalian biliary lineage is specified during liver development. Once this relatively simple epithelium has formed though, how it undergoes morphogenesis to form a complex and branched structure is not clear. Similar to other branched tissues such as the liver and kidney the bile ducts use planar cell polarity signalling to coordinate cell movements; however how these biochemical signals are linked to ductular patterning remains unclear. Here we show that the core planar cell polarity protein, VANGL2 patterns how cell-cell contacts form in the mammalian bile duct and how ductular cells transmit confluent mechanical changes along the length of a duct. This work sheds light on how biological tubes are pattered across mammalian tissues (including within the liver) and will be important in how we promote ductular growth in patients where the duct is mis-patterned or poorly formed. In the developing liver, bipotent epithelial progenitor cells known as hepatoblasts undergo lineage segregation to form the two major epithelial cell types, hepatocytes that constitute the bulk of the liver parenchyma and biliary epithelial cells (cholangiocytes) which comprise the bile duct, a complex tubular network which is critical for normal liver function. Notch and TGFβ signalling promote the formation of a sheet of biliary epithelial cells, the ductal plate that organises into discontinuous tubular structures. How these structures elongate and connect to form a continuous duct remains undefined. We aimed to define the mechanisms by which the ductal plate transitions from simple sheet of epithelial cells to a complex and connected bile duct. By combining single cell RNA sequencing from embryonic mouse livers with genetic tools and organoid models we functionally dissected the role of planar cell polarity in duct patterning. We show that the planar cell polarity protein, VANGL2 is expressed late in intrahepatic bile duct development and patterns the formation of cell-cell contacts between biliary cells. The patterning of these cell contacts regulates the normal polarisation of the actin cytoskeleton within biliary cells and loss of Vangl2-function results in the abnormal distribution of cortical actin remodelling resulting in the failure of bile duct formation. Planar cell polarity is a critical step in the post-specification sculpture of the bile duct and is essential for establishing normal tissue architecture.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».