Morphogenesis and Compartmentalization of the Intestinal Crypt

Sumigray, Kaelyn D.; Terwilliger, Michael; Lechler, Terry

doi:10.1016/j.devcel.2018.03.024

Cited by 137 publications

(157 citation statements)

References 53 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…Cell shape is also an important driver of duct branching. For example, epithelial cells with a high degree of apical constriction are associated with new branch formation on the side of a duct, while cells with a constricted basal surface are correlated with duct bifurcation (Shih et al, 2016;Sumigray et al, 2018). Overall cell shape is dependent on the organization of both the F-actin and MT cytoskeleton networks (Dogterom and Koenderink, 2019), but their respective importance remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Paxillin-dependent regulation of apical-basal polarity in mammary gland morphogenesis

Gulvady

Goreczny

et al. 2019

Development

View full text Add to dashboard Cite

Establishing apical-basal epithelial cell polarity is fundamental for mammary gland duct morphogenesis during mammalian development. While the focal adhesion adapter protein paxillin is a well-characterized regulator of mesenchymal cell adhesion signaling, F-actin cytoskeleton remodeling and single cell migration, its role in epithelial tissue organization and mammary gland morphogenesis in vivo has not been investigated. Here, using a newly developed paxillin conditional knockout mouse model with targeted ablation in the mammary epithelium, in combination with ex vivo threedimensional organoid and acini cultures, we identify new roles for paxillin in the establishment of apical-basal epithelial cell polarity and lumen formation, as well as mammary gland duct diameter and branching. Paxillin is shown to be required for the integrity and apical positioning of the Golgi network, Par complex and the Rab11/MyoVb trafficking machinery. Paxillin depletion also resulted in reduced levels of apical acetylated microtubules, and rescue experiments with the HDAC6 inhibitor tubacin highlight the central role for paxillindependent regulation of HDAC6 activity and associated microtubule acetylation in controlling epithelial cell apical-basal polarity and tissue branching morphogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Paxillin-dependent regulation of apical-basal polarity in mammary gland morphogenesis

Gulvady

Goreczny

et al. 2019

Development

View full text Add to dashboard Cite

show abstract

“…Crypt apical constriction has been reported to initiate crypt morphogenesis in vivo (11). To validate this and to investigate the global morphological changes occurring during crypt formation in organoids, we initially followed their formation with image based time-course experiments at a high spatial-temporal resolution at Day3, Day3.5 and Day4 (15) (Fig.…”

Section: Crypt Morphogenesis Follows Crypt Apical Constriction Villumentioning

confidence: 99%

“…While villus morphogenesis has been well studied, less is known about the mechanism of crypt morphogenesis (4,6,8,9). Apical constriction of the intra-villi tissue has been shown to initiate the early invagination of the crypts (10,11), however, the mechanisms of crypt formation and especially the coordination between cell type emergence and tissue morphogenesis remains to be investigated.…”

mentioning

confidence: 99%

Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis

Yang

Xue

Chan³

et al. 2020

Preprint

View full text Add to dashboard Cite

Intestinal organoids derived from single cells undergo complex crypt-villus patterning and morphogenesis. However, the nature and coordination of the underlying forces remains poorly characterized. Through light-sheet microscopy and mechanical perturbations, we demonstrate that organoid crypt formation coincides with stark lumen volume reduction, which works synergistically with actomyosin-generated crypt apical and villus basal tension to drive morphogenesis. We analyse these mechanical features in a quantitative 3D biophysical model and detect a critical point in actomyosin tensions, above which crypt becomes robust to volume changes. Finally, via single-cell RNA sequencing and pharmacological perturbations, we show that enterocyte-specific expressed sodium/glucose cotransporter modulates lumen volume reduction via promoting cell swelling. Altogether, our study reveals how cell fate-specific changes in osmotic and actomyosin forces coordinate robust organoid morphogenesis. One Sentence Summary:Emergence of region-specific cell fates drive actomyosin patterns and luminal osmotic changes in organoid development.

show abstract

“…the Wnt/β-catenin pathway, hereinafter referred to as Wnt pathway) in regulating the expression of target genes linked to proliferation and differentiation has been extensively studied, both experimentally and theoretically (9)(10)(11)(12). Within the gastrointestinal tract, it is known that Wnt signalling governs proliferative dynamics specific to the lower regions of intestinal crypts (13). The importance of the Wnt pathway in maintaining a healthy cell turnover is clear from studies reporting consequences of Wnt signalling dysfunction (13)(14)(15)(16), with the development of intestinal tumours and polyps linked to mutations in the signalling pathway cascade, and approximately 80% of all human colon tumours reported to show mutations that inactivate the APC gene (17).…”

Section: Introductionmentioning

confidence: 99%

“…Within the gastrointestinal tract, it is known that Wnt signalling governs proliferative dynamics specific to the lower regions of intestinal crypts (13). The importance of the Wnt pathway in maintaining a healthy cell turnover is clear from studies reporting consequences of Wnt signalling dysfunction (13)(14)(15)(16), with the development of intestinal tumours and polyps linked to mutations in the signalling pathway cascade, and approximately 80% of all human colon tumours reported to show mutations that inactivate the APC gene (17). The main cellular effect of activation of the Wnt signalling pathway is to alter the subcellular localisation of β-catenin (9,15).…”

Section: Introductionmentioning

confidence: 99%

Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts: insights from an agent-based model

Ward

Fletcher

Homer

et al. 2018

Preprint

View full text Add to dashboard Cite

24Intestinal crypts are responsible for the total cell renewal of the lining of the intestines, occurring 25 every 4-7 days in humans. This rapid turnover is governed by the complex interplay between 26 signalling pathways and the cell cycle within individual cells in the crypts. The role of Wnt signalling 27 in governing cell proliferation and differentiation in the intestinal crypt has been extensively studied, 28 with increased signalling found towards the lower regions of the crypt. Recent studies have shown 29 that the Wnt signalling gradient found within the crypt may arise as a result of division-based 30 spreading from a Wnt 'reservoir' at the crypt base. The discovery of the Hippo pathway's 31 involvement in maintaining crypt homeostasis is more recent; a mechanistic understanding of Hippo 32 pathway dynamics, and its possible cross-talk with the Wnt pathway, remains lacking. To explore 33 how the interplay between these pathways may control crypt homeostasis and dysplasia we developed 34and analysed a mathematical model coupling an ordinary differential equation description of Wnt and 35Hippo signalling with a cell-based description of cell movement, proliferation and contact inhibition. 36Furthermore, we compared an imposed Wnt gradient with a division-based Wnt gradient model. Our 37 results suggest that Hippo signalling affects the Wnt pathway by reducing the presence of free 38 cytoplasmic β-catenin, causing cell cycle arrest. This process slows the rate of crypt turnover, 39 previously attributed only to mutations in Wnt pathway components commonly observed in colorectal 40 cancers. We also show that a division-based spreading of Wnt can form a Wnt gradient, resulting in 41 proliferative dynamics comparable to imposed-gradient models. This suggests that imposed-gradient 42 models are a reasonable approximation of experimentally observed Wnt gradients, however they 43 provide little insight into the source of Wnt. Finally, a simulated APC double mutant, with 44 misregulated Wnt and Hippo signalling activity, is predicted to be capable of completing a more rapid 45 monoclonal conversion of the crypt than a Wnt-only mutant. 46 47 48 Author summary 50Colorectal cancer is the fourth leading cause of cancer death worldwide. It is generally established 51 that colorectal cancer occurs upon disruption of the dynamics of crypts, tubular indentations lining the 52 walls of the gastrointestinal tract that are responsible for renewal of the intestinal epithelium. Thus, 53understanding the mechanisms that regulate intestinal crypt dynamics is instrumental to understand 54 how colorectal cancer can emerge. We used mathematical modelling to explore how crypt dynamics 55 emerge from the interactions across several biological scales, including mutations that cause an 56 abnormal cell response to changes at the cell or tissue level, cell proliferation and motility within the 57 crypt. Our model describes, in each cell within the crypt, levels and dynamics of genes involved in 58 two signalling pathways -the canonica...

show abstract

Morphogenesis and Compartmentalization of the Intestinal Crypt

Cited by 137 publications

References 53 publications

Paxillin-dependent regulation of apical-basal polarity in mammary gland morphogenesis

Paxillin-dependent regulation of apical-basal polarity in mammary gland morphogenesis

Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis

Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts: insights from an agent-based model

Contact Info

Product

Resources

About