JNK-mediated spindle reorientation in stem cells promotes dysplasia in the aging intestine
Posted on: 27 July 2018
Preprint posted on 11 July 2018
Orientation is important: The cell's fate depends on where you place the spindle.
Selected by Maiko KitaokaCategories: cancer biology, cell biology, developmental biology, genetics
Background Context
Stem cells are a critical population of cells that have the incredible ability to modulate their divisions depending on the requirements set by the physiological context. This ability allows stem cells to actively repair any damage that may have occurred while also maintaining a pool of identical daughter stem cells that are waiting in the wings in case of emergencies. Thus, stem cells can either divide symmetrically, where the two daughter cells have identical fates as new stem cells, or asymmetrically, where one daughter maintains a stem cell fate and the other differentiates to continue tissue repair. Importantly, the orientation of the mitotic spindle and the resulting axis of division has previously been shown to directly impact (a)symmetric divisions and potentially be a key determinant of cell fate. However, the exact mechanisms that regulate this switch and how it may be connected to spindle orientation are still unknown.
Using intestinal stem cells (ISCs) from Drosophila melanogaster, Hu and Jasper exploit the plasticity of this system to investigate the effect of various stresses on ISC divisions as they switch between symmetric and asymmetric divisions. Asymmetric divisions are more predominant during homeostatic tissue regeneration and after tissue damage, while symmetric divisions are favored during growth. JNK signaling has also been implicated in stressful conditions to induce ISC divisions. Taking advantage of the plethora of studies done in various Drosophila tissues, the authors have pieced together a multi-layered mechanism that includes JNK signaling, spindle orientation proteins, and transcriptional repression.
Key findings
First, the authors established that spindle orientation can change depending on the environmental context. They examined three types of situations:
- Starvation and refeeding cycles to stimulate growth, termed “adaptive resizing”.
- Infection with Ecc15, a bacterium known to damage the intestine and stimulate regeneration.
- Exposure to paraquat to induce oxidative stress, a more severe condition that results in epithelial dysplasia and is reminiscent of aging dysfunction.
For each of these conditions, they determined the predominant spindle orientation by measuring the angle created between the pole-to-pole axis of the spindle and the epithelial basement membrane. Measurements near 0° are planar to the basement membrane, indicating symmetric divisions. In contrast, asymmetric divisions are oblique with a much larger angle. They determined that normal, homeostatic conditions had oblique spindles (asymmetric divisions), while periods of growth had planar (symmetric) divisions. Ecc15 infection led to mostly oblique spindles as well, similar to homeostatic conditions, while the more severe paraquat exposure led to a planar shift in orientation. Live imaging revealed that oblique spindles are oriented dynamically during mitosis.
ISC divisions can be either symmetric, where the angle is close to 0°, or asymmetric. From Figure 1.
In order to elucidate a mechanism that controls spindle orientation, the authors tested whether JNK activation led to increased planar spindles. Increasing JNK activity through genetic manipulations increased ISC proliferation and induced planar spindles, importantly phenocopying the results during adaptive resizing or paraquat exposure.
As the authors continued to investigate the role of JNK activation in spindle orientation, they found two unique mechanisms involved. First, previous transcriptomic data suggested that a kinesin, Kif1a, was decreased when JNK was activated. Indeed, Kif1a depletion increased planar spindle orientation, but more strikingly, overexpression of Kif1a after paraquat exposure was sufficient to block planar spindle orientations. Secondly, the authors focused on Wdr62, a centrosome-associated protein that has been shown to recruit JNK to the spindle in mammalian glial cells to orient the spindle. Overexpression of Wdr62 caused spindles to become planar, while RNAi depletion was sufficient to prevent spindles from becoming planar in JNK- or paraquat-induced stress conditions. Using mosaic flies, only clones homozygous for Wdr62 deficiency maintained oblique spindle orientations despite paraquat exposure, suggesting a key role for Wdr62 to control spindle orientation under stressful, JNK-activating conditions. Of note, no obvious spindle assembly defects were observed, although Wdr62-deficient clones resulted in smaller cell sizes.
Both of these mechanisms are compelling arguments supporting the role of JNK signaling in spindle orientation, and the authors add another layer to this process by examining LGN and NuMA (Pins and Mud in Drosophila, respectively), two classically-known spindle orientation proteins. Depletion of either increased the number of planar spindles, and interestingly, NuMA localization shifts to the spindle after paraquat treatment and JNK activation and remains at the cortex when JNK signaling is eliminated. This reveals that JNK activity promotes release of NuMA from the cell cortex to the spindle, resulting in planar orientation of spindles.
Finally, the authors examined the effect of JNK signaling on spindle orientation in aging animals, where they saw that the intestinal epithelium of older flies had increased planar spindle orientations and increased mitotic activity as well. Strikingly, they were able to rescue the oblique spindle orientation when JNK activation is repressed, Wdr62 is depleted, or Kif1a is overexpressed. This demonstrates clearly that over-activation of JNK signaling and its subsequent interactions with Wdr62 and repression of Kif1a causes increased planar cell divisions and aberrant cell fates during the natural aging process. These rescue experiments also demonstrate that spindle orientation defects are potentially reversible. In addition to the subcellular rescue of spindle orientation, the authors asked if these genetic manipulations were sufficient to protect the integrity of the intestinal tissue, which normally loses its barrier during aging. In the aptly-named Smurf assay, older flies were fed food with a blue dye that can spread to the entire body if the intestinal barrier function declines, causing them to turn blue. The authors found that the knockdown of Wdr62 or overexpression of Kif1a resulted in decreased numbers of aged Smurf flies, indicating better intestinal barrier health. Thus, remarkably, manipulating spindle orientation is sufficient to prevent the loss of tissue integrity and function in the intestine.
In this preprint, Hu and Jasper demonstrate a large amount of work that went into dissecting the intricate mechanisms that orient the mitotic spindle during various stress conditions, as well as larger scale physiological consequences of perturbing these mechanisms. The authors tackled a large, potentially very convoluted process, especially given how many other pathways JNK signaling is involved in, and importantly demonstrated the plasticity and reversibility of this process, as spindle orientation can clearly respond to environmental cues and even help maintain tissue function over a longer timescale.
Questions for the authors
The mechanisms described here are very separate, where JNK activation is the main connection between all of them. How are the mechanisms that involve Kif1a, Wdr62, and NuMA/Mud connected to each other, if at all? Which of these mechanisms begins to “fall apart” during aging to lead to more planar, rather than oblique, divisions – is it one specific mechanism or sequential accumulation of all three?
Why would Wdr62 deficiency lead to smaller clones despite lack of spindle assembly defects? Was this also seen in the RNAi depletion experiments?
What is the normal, known role of Kif1a in mediating spindle assembly or orientation?
doi: https://doi.org/10.1242/prelights.3625
Read preprintSign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cancer biology category:
Integrin conformation-dependent neutrophil slowing obstructs the capillaries of the pre-metastatic lung in a model of breast cancer
Simon Cleary
Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects
Teodora Piskova
Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma
Jessica Chevallier
Also in the cell biology category:
The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites
Felipe Del Valle Batalla
Pharyngeal neuronal mechanisms governing sour taste perception in Drosophila melanogaster
Matthew Davies
Feedback regulation by the RhoA-specific GEF ARHGEF17 regulates actomyosin network disassembly
Vibha SINGH
Also in the developmental biology category:
Specialized signaling centers direct cell fate and spatial organization in a limb organoid model
Ryan Harrison
Adult caudal fin shape is imprinted in the embryonic fin fold
Isabella Cisneros
TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
Reinier Prosee
Also in the genetics category:
Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA
Leeba Ann Chacko
The bat Influenza A virus subtype H18N11 induces nanoscale MHCII clustering upon host cell attachment
Mitchell Sarmie, Mohammed A. Jalloh
Enhancer-driven cell type comparison reveals similarities between the mammalian and bird pallium
Rodrigo Senovilla-Ganzo
preListscancer biology category:
in theBSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
List by | Osvaldo Contreras |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
List by | Alex Eve |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
List by | Rob Hynds |
Anticancer agents: Discovery and clinical use
Preprints that describe the discovery of anticancer agents and their clinical use. Includes both small molecules and macromolecules like biologics.
List by | Zhang-He Goh |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
List by | Joseph Jose Thottacherry |
Also in the cell biology category:
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
List by | Sandra Franco Iborra |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
List by | Dey Lab, Amanda Haage |
Also in the developmental biology category:
BSDB/GenSoc Spring Meeting 2024
A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.
List by | Joyce Yu, Katherine Brown |
GfE/ DSDB meeting 2024
This preList highlights the preprints discussed at the 2024 joint German and Dutch developmental biology societies meeting that took place in March 2024 in Osnabrück, Germany.
List by | Joyce Yu |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
List by | Nadja Hümpfer et al. |
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
List by | Nándor Lipták |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
List by | Alex Eve |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
List by | Jesus Victorino |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
List by | Alex Eve |
Society for Developmental Biology 79th Annual Meeting
Preprints at SDB 2020
List by | Irepan Salvador-Martinez, Martin Estermann |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
List by | Ana Dorrego-Rivas |
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
List by | Paul Gerald L. Sanchez and Stefano Vianello |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
EDBC Alicante 2019
Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.
List by | Sergio Menchero et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
List by | Dey Lab |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
List by | Alex Eve |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
List by | Rob Hynds |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
List by | Alex Eve |
Pattern formation during development
The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.
List by | Alexa Sadier |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
List by | Dey Lab |
Zebrafish immunology
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.
List by | Shikha Nayar |
Also in the genetics category:
BSDB/GenSoc Spring Meeting 2024
A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.
List by | Joyce Yu, Katherine Brown |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University
This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.
List by | Nándor Lipták |
20th “Genetics Workshops in Hungary”, Szeged (25th, September)
In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf
List by | Nándor Lipták |
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
List by | Nándor Lipták |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
List by | Jesus Victorino |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |