Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice.

The Journal of Clinical Investigation
Ryotaro SakamoriNan Gao

Abstract

The constant self renewal and differentiation of adult intestinal stem cells maintains a functional intestinal mucosa for a lifetime. However, the molecular mechanisms that regulate intestinal stem cell division and epithelial homeostasis are largely undefined. We report here that the small GTPases Cdc42 and Rab8a are critical regulators of these processes in mice. Conditional ablation of Cdc42 in the mouse intestinal epithelium resulted in the formation of large intracellular vacuolar structures containing microvilli (microvillus inclusion bodies) in epithelial enterocytes, a phenotype reminiscent of human microvillus inclusion disease (MVID), a devastating congenital intestinal disorder that results in severe nutrient deprivation. Further analysis revealed that Cdc42-deficient stem cells had cell division defects, reduced capacity for clonal expansion and differentiation into Paneth cells, and increased apoptosis. Cdc42 deficiency impaired Rab8a activation and its association with multiple effectors, and prevented trafficking of Rab8a vesicles to the midbody. This impeded cytokinesis, triggering crypt apoptosis and disrupting epithelial morphogenesis. Rab8a was also required for Cdc42-GTP activity in the intestinal epithelium...Continue Reading

References

Dec 1, 1990·Molecular and Cellular Biology·P ChavrierM Zerial
Nov 1, 1996·The Journal of Cell Biology·O UllrichR G Parton
Jan 1, 1997·Current Biology : CB·D N DrechselM Glotzer
Apr 12, 2001·BMC Developmental Biology·S SrinivasF Costantini
Jun 20, 2001·Current Biology : CB·M GottaJ Ahringer
Sep 6, 2003·Traffic·Karen C Hobdy-HendersonJames R Goldenring
Feb 8, 2005·Trends in Cell Biology·Roger AlbertsonWilliam Sullivan
Mar 3, 2006·Genes & Development·Xunwei WuCord Brakebusch
Nov 16, 2006·Journal of Cell Science·Katarina HattulaJohan Peränen
Jul 20, 2007·Cell Cycle·Sergio RinconPilar Perez
Jul 30, 2008·Developmental Biology·Anna Bielak-ZmijewskaEwa Borsuk
Aug 30, 2008·Nature Genetics·Thomas MüllerAndreas R Janecke
Mar 11, 2009·Molecular and Cellular Biology·Masaru MitsushimaEisuke Nishida
Apr 24, 2009·Developmental Cell·Nan GaoKlaus H Kaestner
Dec 5, 2009·Journal of the American Society of Nephrology : JASN·Veronique DouardRonaldo P Ferraris
Mar 24, 2010·Proceedings of the National Academy of Sciences of the United States of America·Andreas KnödlerWei Guo
May 19, 2010·The Journal of Cell Biology·Alejo E Rodriguez-FraticelliFernando Martín-Belmonte
Jun 17, 2010·Genes & Development·Nan Gao, Klaus H Kaestner
Oct 5, 2010·Nature Cell Biology·David M BryantKeith E Mostov
Feb 2, 2011·Proceedings of the National Academy of Sciences of the United States of America·Joseph T RolandJames R Goldenring
Feb 9, 2011·The Journal of Biological Chemistry·Joanne DurganAlan Hall
May 10, 2011·Trends in Cell Biology·Amlan Das, Wei Guo
Nov 15, 2011·Science·Norifumi TakedaJonathan A Epstein

❮ Previous
Next ❯

Citations

Dec 12, 2013·Nature Reviews. Molecular Cell Biology·Nick Barker
Jan 9, 2014·Human Molecular Genetics·Barbara VaccaAndré Le Bivic
Jun 4, 2014·The Journal of Clinical Investigation·Byron C KnowlesMitchell D Shub
Sep 24, 2015·Proceedings of the National Academy of Sciences of the United States of America·Kerstin SchneebergerSabine Middendorp
Mar 12, 2016·Journal of Experimental & Clinical Cancer Research : CR·Yudan Chi, Dongming Zhou
Sep 10, 2013·Human Mutation·K Joeri van der VeldeSven C D van Ijzendoorn
Dec 9, 2014·Small GTPases·Philippe M Duquette, Nathalie Lamarche-Vane
Jun 28, 2015·Journal of Hepatology·Paul Gissen, Irwin M Arias
May 6, 2015·Trends in Cell Biology·Arend W OvereemSven C D van IJzendoorn
May 9, 2012·Cell Stem Cell·Maria Carolina FlorianHartmut Geiger
Jun 10, 2016·Traffic·Alvaro Román-Fernández, David M Bryant
Sep 15, 2016·Cellular and Molecular Life Sciences : CMLS·Rocío López-PosadasImke Atreya
May 18, 2016·Scientific Reports·Marie-Pier TetreaultJonathan P Katz
Jul 24, 2015·Scientific Reports·Fernando Cartón-GarcíaDiego Arango
Feb 19, 2017·Cold Spring Harbor Perspectives in Biology·Leon J KlunderSven C D van IJzendoorn
Mar 30, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xing-Hua XiaoLi-Xia Xiong
Jan 10, 2016·Disease Models & Mechanisms·Arend W OvereemSven C D van IJzendoorn
Jul 7, 2016·Development·Katherine D WaltonDeborah L Gumucio
Dec 13, 2018·Molecular Biology of the Cell·Akiko ShitaraRoberto Weigert
Apr 14, 2020·Small GTPases·Isabella R BlumJean M Wilson
May 4, 2017·Oncotarget·Fatima Valdés-MoraJuan Carlos Lacal
Jan 13, 2015·American Journal of Physiology. Gastrointestinal and Liver Physiology·Christa N GrantTracy C Grikscheit
Dec 26, 2018·World Journal of Gastroenterology : WJG·Wen-Juan TangYing Huang
Oct 21, 2017·Frontiers in Immunology·Rocío López-PosadasNathalie Britzen-Laurent
Mar 29, 2018·Disease Models & Mechanisms·Kerstin SchneebergerSabine Middendorp
Apr 15, 2020·Nature Microbiology·Kyle BittingerGary D Wu
Sep 27, 2014·American Journal of Physiology. Gastrointestinal and Liver Physiology·Dmitri KravtsovPedro J Salas

❮ Previous
Next ❯

Methods Mentioned

BETA
biopsy
GTPase
GTPases
flow cytometry
electrophoresis
pull-down
Transfection

Software Mentioned

LS
ImageJ
ImageStream IDEAS

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Adult Stem Cells

Adult stem cells reside in unique niches that provide vital cues for their survival, self-renewal, and differentiation. They hold great promise for use in tissue repair and regeneration as a novel therapeutic strategies. Here is the latest research.