Identification and characterization of novel determinants of epithelial apical-basal polarity and lumen formation
Bibliographic record
Abstract
Epithelial cells line most organ and tissue surfaces and provide an essential barrier that separates physiological compartments.A nearly universal feature of epithelial cells is their polarization into distinct apical and basolateral membrane domains that allows groups of cells to organize into complex structures such as tubes and acini with a characteristic central lumen.This process requires that cells coordinately orient their polarity axis so that the basolateral domain is on the outside and apical domain inside epithelial structures.However, the cues that initiate internalization of apical proteins from the periphery to establish an internal apical site are incompletely understood.To identify potential novel regulators of apical-basal polarity and lumen formation, I used a biotin identification (BioID) approach coupled with mass spectrometry in epithelial cells cultured in a three-dimensional matrix.I report in this thesis several novel proteins involved in lumen formation, including CD13, PARD3B, RALB, and HRNR, each of which is necessary for epithelial organization and lumen formation.I also identified PTPN14 as a novel polarityassociated protein, which regulates epithelial organization during oncogene-induced malignant transformation.I report that CD13 (Aminopeptidase N/APN/ANPEP) associates with the apical Crumbs/Par6.Loss of CD13 induces an inverted polarity phenotype in which apical components fail to accumulate at the appropriate location during cell division.I propose that CD13 acts as a surface membrane receptor for Rab11-mediated endocytosis of apical cargo that is necessary to reorient apical proteins from the periphery to internal sites necessary for lumen formation. RésuméLes cellules épithéliales tapissent la plupart des organes ainsi que la surface des tissus et assurent une fonction de barrière indispensable, afin de séparer les compartiments physiologiques.Une caractéristique presque universelle des cellules épithéliales est leur polarisation en domaines membranaires apicaux et basolatéraux distincts, qui permettent aux groupes de cellules de s'organiser en structures complexes, telles que des tubes et des acini avec une lumière centrale caractéristique.Ce processus requiert que les cellules orientent leur axe de polarité de façon coordonnée, afin que le domaine basolatéral se situe à l'extérieur et le domaine apical à l'intérieur des structures épithéliales.Cependant, les signaux qui initient l'internalisation des protéines apicales à partir de la périphérie, afin d'établir un site apical interne, ne sont pas encore complètement compris.Afin d'identifier de potentiels nouveaux régulateurs de la polarité apico-basale et de la formation de la lumière, j'ai utilisé une approche d'identification de la biotine (BioID) couplée à la spectrométrie de masse, sur des cellules épithéliales cultivées dans une matrice en trois dimensions.Je rapporte dans cette thèse de nombreuses nouvelles protéines impliquées dans la formation de la lumière, incluant CD13, PARD3B, RALB et HRNR, chacune étant nécessaire à l'organisation épithéliale et à la formation de la lumière.J'ai également identifié PTPN14 comme une nouvelle protéine associée à la polarité, qui régule l'organisation épithéliale au cours de la transformation maligne, induite par un oncogène.J'ai montré que CD13 (Aminopeptidase N/APN/ANPEP) s'associe au niveau apical avec Crumbs/Par6.La perte de CD13 induit un phénotype de polarité inversée dans lequel les composants apicaux ne s'accumulent pas au bon endroit, au cours de la division cellulaire.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".