Van Gogh-like 2 is essential for the architectural patterning of the mammalian biliary tree
Bibliographic record
Abstract
•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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".