p120ctn-Mediated Organ Patterning Precedes and Determines Pancreatic Progenitor Fate

Nyeng, Pia; Heilmann, Silja; Löf-Öhlin, Zarah M.; Fransén-Pettersson, Nina; Hermann, Florian Malte; Reynolds, Albert B.; Semb, Henrik

doi:10.1016/j.devcel.2019.02.005

Cited by 29 publications

(38 citation statements)

References 60 publications

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“…With our approach using zebrafish larvae, it is possible to visualize not only the whole endocrine cell population in relation to the ductal progenitor compartment, but also the morphology of single endocrine cells in 3D. Consistent with observations from explant studies showing that beta cells produce cytoplasmic protrusions and move along the duct to join other beta cells (Nyeng et al, 2019), our studies revealed that endocrine cells stay in proximity to the duct, and use dynamic protrusions to initiate cell-cell contacts which appear to direct cell coalescence.…”

Section: Discussionsupporting

confidence: 77%

“…The membrane targeted memKate co-localized with EGFP in the principal and secondary islets. In loosely associated secondary islet cells, the memKate highlighted cell contours as well as protrusions and fine cell-cell connections ( Figures 2I,J, arrows), which are proposed to play a functional role in the assembly process (Freudenblum et al, 2018;Nyeng et al, 2019).…”

Section: A Tool For Highlighting Cell Morphology During Islet Formationmentioning

confidence: 99%

“…The islets, clustered endocrine cells enveloped within the exocrine tissue, develop from progressive coalescence of differentiating progenitor cells that emerge from the ductal epithelium. While previous work suggested that progenitors actively migrate through the pancreatic mesenchyme during islet morphogenesis (Puri and Hebrok, 2007;Kesavan et al, 2014;Pauerstein et al, 2017), recent evidence reveals that clustering occurs in proximity to the pancreatic duct, either concurrent with cell exit (Sharon et al, 2019), or following movements along the ductal epithelium (Nyeng et al, 2019). Imaging studies in vivo and in explants have reported formation of dynamic protrusions in endocrine cells (Bechard et al, 2016;Bankaitis et al, 2018;Freudenblum et al, 2018), but their role in islet formation has not been fully defined.…”

Section: Introductionmentioning

confidence: 99%

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Inducible Mosaic Cell Labeling Provides Insights Into Pancreatic Islet Morphogenesis

Freudenblum

Meyer

Kimmel

2020

Front. Cell Dev. Biol.

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Pancreatic islets, discrete microorgans embedded within the exocrine pancreas, contain beta cells which are critical for glucose homeostasis. Loss or dysfunction of beta cells leads to diabetes, a disease with expanding global prevalence, and for which regenerative therapies are actively being pursued. Recent efforts have focused on producing mature beta cells in vitro, but it is increasingly recognized that achieving a faithful three-dimensional islet structure is crucial for generating fully functional beta cells. Our current understanding of islet morphogenesis is far from complete, due to the deep internal location of the pancreas in mammalian models, which hampers direct visualization. Zebrafish is a model system well suited for studies of pancreas morphogenesis due to its transparency and the accessible location of the larval pancreas. In order to further clarify the cellular mechanisms of islet formation, we have developed new tools for in vivo visualization of single-cell dynamics. Our results show that clustering islet cells make contact and interconnect through dynamic actin-rich processes, move together while remaining in close proximity to the duct, and maintain high protrusive motility after forming clusters. Quantitative analyses of cell morphology and motility in 3-dimensions lays the groundwork to define therapeutically applicable factors responsible for orchestrating the morphogenic behaviors of coalescing endocrine cells.

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Section: Discussionsupporting

confidence: 77%

Section: A Tool For Highlighting Cell Morphology During Islet Formationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inducible Mosaic Cell Labeling Provides Insights Into Pancreatic Islet Morphogenesis

Freudenblum

Meyer

Kimmel

2020

Front. Cell Dev. Biol.

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“…These clusters represent distinct pancreatic lineages at different embryonic stages, when the pancreatic epithelium is composed of MPCs. The MPCs undergo step-wise lineage restrictions and segregation into two distinct tip and trunk domains, which further differentiate into acinar and duct/EPs, respectively (Nyeng et al, 2019;Zhou et al, 2007). EPs then differentiate into Fev high cells that subsequently generate different types of endocrine hormone + cells (Fig.…”

Section: Single Cell Rna-seq Of the Embryonic Ep-enriched Pancreatic mentioning

confidence: 99%

Comprehensive single cell mRNA profiling reveals a detailed roadmap for pancreatic endocrinogenesis

et al. 2019

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Deciphering mechanisms of endocrine cell induction, specification and lineage allocation in vivo will provide valuable insights into how the islets of Langerhans are generated. Currently, it is ill defined how endocrine progenitors segregate into different endocrine subtypes during development. Here, we generated a novel neurogenin 3 (Ngn3)-Venus fusion (NVF) reporter mouse line, that closely mirrors the transient endogenous Ngn3 protein expression. To define an in vivo roadmap of endocrinogenesis, we performed single cell RNA sequencing of 36,351 pancreatic epithelial and NVF + cells during secondary transition. This allowed Ngn3 low endocrine progenitors, Ngn3 high endocrine precursors, Fev + endocrine lineage and hormone + endocrine subtypes to be distinguished and timeresolved, and molecular programs during the step-wise lineage restriction steps to be delineated. Strikingly, we identified 58 novel signature genes that show the same transient expression dynamics as Ngn3 in the 7260 profiled Ngn3-expressing cells. The differential expression of these genes in endocrine precursors associated with their cell-fate allocation towards distinct endocrine cell types. Thus, the generation of an accurately regulated NVF reporter allowed us to temporally resolve endocrine lineage development to provide a fine-grained single cell molecular profile of endocrinogenesis in vivo.

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“…From the analysis of clones traced from E12.5 to E14.5, E12.5 to E15.5 and E12.5 to E18.5, combined with insulin/DBA and glucagon/DBA immunostaining, we did not observe insulin+ or glucagon+ cell-contributing clones in PDE or ducts (Supplementary Fig. 2l–r ), although PDE localisation and endocrine lineage segregation might be temporally correlated 33 ).…”

Section: Resultsmentioning

confidence: 86%

Tracing the cellular basis of islet specification in mouse pancreas

et al. 2020

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Pancreatic islets play an essential role in regulating blood glucose level. Although the molecular pathways underlying islet cell differentiation are beginning to be resolved, the cellular basis of islet morphogenesis and fate allocation remain unclear. By combining unbiased and targeted lineage tracing, we address the events leading to islet formation in the mouse. From the statistical analysis of clones induced at multiple embryonic timepoints, here we show that, during the secondary transition, islet formation involves the aggregation of multiple equipotent endocrine progenitors that transition from a phase of stochastic amplification by cell division into a phase of sublineage restriction and limited islet fission. Together, these results explain quantitatively the heterogeneous size distribution and degree of polyclonality of maturing islets, as well as dispersion of progenitors within and between islets. Further, our results show that, during the secondary transition, α- and β-cells are generated in a contemporary manner. Together, these findings provide insight into the cellular basis of islet development.

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p120ctn-Mediated Organ Patterning Precedes and Determines Pancreatic Progenitor Fate

Cited by 29 publications

References 60 publications

Inducible Mosaic Cell Labeling Provides Insights Into Pancreatic Islet Morphogenesis

Inducible Mosaic Cell Labeling Provides Insights Into Pancreatic Islet Morphogenesis

Comprehensive single cell mRNA profiling reveals a detailed roadmap for pancreatic endocrinogenesis

Tracing the cellular basis of islet specification in mouse pancreas

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