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RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells of mice

ABSTRACT: RAB11 small GTPases and associated recycling endosomes localize to mitotic spindles and have been implicated in the regulation of mitosis. However, the physiological significance of this function has not been addressed in mammals. We use newly engineered mouse models to investigate intestinal epithelial renewal in the absence of one or both of RAB11 family members, i.e. Rab11a and Rab11b. In contrast to single-knockout mice, the double-knockout animals demonstrate defects in cell cycle entry and significant mitotic arrest followed by apoptosis, and lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates reveals a shared interactome that includes mitotic spindle microtubule regulators. Disruption of Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may also be utilized to control homeostasis and renewal of other mammalian tissues.

SUBMITTER: Mr. Ivor, G Joseph

PROVIDER: S-SCDT-10_15252-EMBR_202256240 | biostudies-other |

REPOSITORIES: biostudies-other

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RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells.

Project description:RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.

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Control of Intestinal Cell Fate by Dynamic Mitotic Spindle Repositioning Influences Epithelial Homeostasis and Longevity.

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Lineage Specification from Prostate Progenitor Cells Requires Gata3-Dependent Mitotic Spindle Orientation.

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Mammalian neurogenesis requires Treacle-Plk1 for precise control of spindle orientation, mitotic progression, and maintenance of neural progenitor cells.

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RAB11A and RAB11B redundantly regulate mitotic spindle function in dividing tissue progenitor cells

Project description:To investigate the role of Rab11 isoforms in intestinal epithelial cells and its downstream effects on intestinal homeostasis.

2023-06-09 | GSE232493 | GEO

Automated mitotic spindle tracking suggests a link between spindle dynamics, spindle orientation, and anaphase onset in epithelial cells.

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