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Molinas, A., Heil, S. & Koch, S. (2021). The Candidate IBD Risk Gene CCNY Is Dispensable for Intestinal Epithelial Homeostasis. Cells, 10(9), Article ID 2330.
Open this publication in new window or tab >>The Candidate IBD Risk Gene CCNY Is Dispensable for Intestinal Epithelial Homeostasis
2021 (English)In: Cells, E-ISSN 2073-4409, Vol. 10, no 9, article id 2330Article in journal (Refereed) Published
Abstract [en]

The CCNY gene, which encodes cyclin Y, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Cyclin Y promotes Wnt/β-catenin signaling and autophagy, which are critical for intestinal epithelial cell (IEC) homeostasis, and may thereby contribute to wound repair in colitis. However, whether cyclin Y has an essential function in IECs is unknown. We, therefore, investigated the epithelial injury response and mucosal regeneration in mice with conditional knock-out of Ccny in the intestinal epithelium. We observed that Ccny-deficient mice did not exhibit any differences in cell proliferation and disease activity compared to wild-type littermates in the dextran sulfate sodium (DSS) colitis model. Complementary in vitro experiments showed that loss of CCNY in model IECs did not affect Wnt signaling, cell proliferation, or autophagy. Additionally, we observed that expression of the cyclin-Y-associated cyclin-dependent kinase (CDK) 14 is exceedingly low specifically in IEC. Collectively, these results suggest that cyclin Y does not contribute to intestinal epithelial homeostasis, possibly due to low levels of specific CDKs in these cells. Thus, it is unlikely that CCNY mutations are causatively involved in IBD pathogenesis.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
CDK14, Wnt signaling, colitis, inflammatory bowel diseases
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-179681 (URN)10.3390/cells10092330 (DOI)000699463000001 ()34571979 (PubMedID)2-s2.0-85115891963 (Scopus ID)
Note

Funding: Knut and AliceWallenberg Foundation (KAW)Knut & Alice Wallenberg Foundation; Swedish Research Council (VR)Swedish Research Council; Swedish Cancer Society (Cancerfonden)Swedish Cancer Society; European Crohns and Colitis Organisation (ECCO)

Available from: 2021-09-29 Created: 2021-09-29 Last updated: 2021-10-29Bibliographically approved
Escudero-Hernández, C., van Beelen Granlund, A., Bruland, T., Sandvik, A. K., Koch, S., Østvik, A. E. & Münch, A. (2021). Transcriptomic profiling of collagenous colitis identifies hallmarks of non-destructive inflammatory bowel disease.. Cellular and molecular gastroenterology and hepatology, 12(2), 665-687, Article ID S2352-345X(21)00082-5.
Open this publication in new window or tab >>Transcriptomic profiling of collagenous colitis identifies hallmarks of non-destructive inflammatory bowel disease.
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2021 (English)In: Cellular and molecular gastroenterology and hepatology, ISSN 2352-345X, Vol. 12, no 2, p. 665-687, article id S2352-345X(21)00082-5Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: The pathophysiology of the inflammatory bowel disease collagenous colitis (CC) is poorly described. Our aim was to use RNA sequencing of mucosal samples from patients with active CC, CC in remission, refractory CC, ulcerative colitis (UC), and controls to gain insight into CC pathophysiology, identify genetic signatures linked to CC, and uncover potentially druggable disease pathways.

METHODS: We performed whole transcriptome sequencing of CC samples from patients before and during treatment with the corticosteroid drug budesonide, CC steroid-refractory patients, UC patients, and healthy controls (n=9-13). Bulk mucosa and laser-captured microdissected intestinal epithelial cell (IEC) gene expression were analyzed by gene-set enrichment and gene-set variation analyses to identify significant pathways and cells, respectively, altered in CC. Leading genes and cells were validated using reverse transcription quantitative PCR and/or immunohistochemistry.

RESULTS: We identified an activation of the adaptive immune response to bacteria and viruses in active CC that could be mediated by dendritic cells. Moreover, IECs display hyperproliferation and increased antigen presentation in active CC. Further analysis revealed that genes related to the immune response (DUOX2, PLA2G2A, CXCL9), DNA transcription (CTR9), protein processing (JOSD1, URI1) and ion transport (SLC9A3) remained dysregulated even after budesonide-induced remission. Budesonide-refractory CC patients fail to restore normal gene expression, and displayed a transcriptomic profile close to UC.

CONCLUSIONS: Our study confirmed the implication of innate and adaptive immune responses in CC, governed by IECs and dendritic cells, respectively; and identified ongoing epithelial damage. Refractory CC could share pathomechanisms with UC.

Place, publisher, year, edition, pages
American Gastroenterological Association, 2021
Keywords
Epithelial cells, RNA sequencing, microscopic colitis, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-175398 (URN)10.1016/j.jcmgh.2021.04.011 (DOI)000680864400014 ()33930606 (PubMedID)
Note

Funding: Ferring Pharmaceuticals (Switzerland)Ferring Pharmaceuticals; ALF (Region Ostergotland, Sweden); Magtarmfonden (Swedish Society of Gastroenterolgy); Mucosal Infection and Inflammation Centre (Linkoping University) postdoctoral fellowship; Knut and Alice Wallenberg Foundation (Sweden)Knut & Alice Wallenberg Foundation; Norwegian Research Council grant FRIPRO [262549]; NTNU Outstanding Academic Fellows Programme; Liaison committee

Available from: 2021-05-03 Created: 2021-05-03 Last updated: 2023-12-28Bibliographically approved
Moparthi, L. & Koch, S. (2020). A uniform expression library for the exploration of FOX transcription factor biology. Differentiation, 115, 30-36, Article ID S0301-4681(20)30046-3.
Open this publication in new window or tab >>A uniform expression library for the exploration of FOX transcription factor biology
2020 (English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 115, p. 30-36, article id S0301-4681(20)30046-3Article in journal (Refereed) Published
Abstract [en]

Forkhead box (FOX) family transcription factors play essential roles in development, tissue homeostasis, and disease. Although the biology of several FOX proteins has been studied in depth, it is unclear to what extent these findings apply to even closely related family members, which frequently exert overlapping but non-redundant functions. To help address this question, we have generated a uniform, ready-to-use expression library of all 44 human FOX transcription factors with a convenient peptide tag for parallel screening assays. In addition, we have generated multiple universal forkhead box reporter plasmids, which can be used to monitor the transcriptional activity of most FOX proteins with high fidelity. As a proof-of-principle, we use our plasmid library to identify the DNA repair protein XRCC6/Ku70 as a selective FOX interaction partner and regulator of FOX transcriptional activity. We believe that these tools, which we make available via the Addgene plasmid repository, will considerably expedite the investigation of FOX protein biology.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
DNA repair, Forkhead box, Ku complex, Luciferase reporter, Transcription
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-168954 (URN)10.1016/j.diff.2020.08.002 (DOI)000573910300004 ()32858261 (PubMedID)2-s2.0-85089731395 (Scopus ID)
Note

Funding agencies: Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; Rotary Club Borgholm; Lions Foundation

Available from: 2020-09-03 Created: 2020-09-03 Last updated: 2020-10-19Bibliographically approved
Escudero-Hernández, C., Münch, A., Østvik, A.-E., Granlund, A. v. & Koch, S. (2020). The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis. Journal of Crohn's & Colitis, 14(7), 962-973
Open this publication in new window or tab >>The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis
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2020 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 14, no 7, p. 962-973Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: Diarrhoea is a common, debilitating symptom of gastrointestinal disorders. Pathomechanisms probably involve defects in trans-epithelial water transport, but the role of aquaporin [AQP] family water channels in diarrhoea-predominant diseases is unknown. We investigated the involvement of AQPs in the pathobiology of collagenous colitis [CC], which features chronic, watery diarrhoea despite overtly normal intestinal epithelial cells [IECs].

METHODS: We assessed the expression of all AQP family members in mucosal samples of CC patients before and during treatment with the corticosteroid drug budesonide, steroid-refractory CC patients and healthy controls. Samples were analysed by genome-wide mRNA sequencing [RNA-seq] and quantitative real-time PCR [qPCR]. In some patients, we performed tissue microdissection followed by RNA-seq to explore the IEC-specific CC transcriptome. We determined changes in the protein levels of the lead candidates in IEC by confocal microscopy. Finally, we investigated the regulation of AQP expression by corticosteroids in model cell lines.

RESULTS: Using qPCR and RNA-seq, we identified loss of AQP8 expression as a hallmark of active CC, which was reverted by budesonide treatment in steroid-responsive but not refractory patients. Consistently, decreased AQP8 mRNA and protein levels were observed in IECs of patients with active CC, and steroid drugs increased AQP8 expression in model IECs. Moreover, low APQ8 expression was strongly associated with higher stool frequency in CC patients.

CONCLUSION: Down-regulation of epithelial AQP8 may impair water resorption in active CC, resulting in watery diarrhoea. Our results suggest that AQP8 is a potential drug target for the treatment of diarrhoeal disorders.

Place, publisher, year, edition, pages
Oxford University Press, 2020
Keywords
Microscopic colitis, RNA sequencing, permeability
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-168650 (URN)10.1093/ecco-jcc/jjaa020 (DOI)000582311700011 ()32016376 (PubMedID)2-s2.0-85089127129 (Scopus ID)
Available from: 2020-08-27 Created: 2020-08-27 Last updated: 2021-03-17Bibliographically approved
Koch, S. (2019). Who controls the Wnt?. Differentiation, 108
Open this publication in new window or tab >>Who controls the Wnt?
2019 (English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 108Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-160173 (URN)10.1016/j.diff.2019.06.001 (DOI)000481618600001 ()31239179 (PubMedID)2-s2.0-85067570066 (Scopus ID)
Available from: 2019-09-09 Created: 2019-09-09 Last updated: 2019-09-17Bibliographically approved
Martins, L. R., Bung, R. K., Koch, S., Richter, K., Schwarzmüller, L., Terhardt, D., . . . Scholl, C. (2018). Stk33 is required for spermatid differentiation and male fertility in mice. Developmental Biology, 433(1), 84-93
Open this publication in new window or tab >>Stk33 is required for spermatid differentiation and male fertility in mice
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2018 (English)In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 433, no 1, p. 84-93Article in journal (Refereed) Published
Abstract [en]

Spermiogenesis is the final phase during sperm cell development in which round spermatids undergo dramatic morphological changes to generate spermatozoa. Here we report that the serine/threonine kinase Stk33 is essential for the differentiation of round spermatids into functional sperm cells and male fertility. Constitutive Stk33 deletion in mice results in severely malformed and immotile spermatozoa that are particularly characterized by disordered structural tail elements. Stk33 expression first appears in primary spermatocytes, and targeted deletion of Stk33 in these cells recapitulates the defects observed in constitutive knockout mice, confirming a germ cell-intrinsic function. Stk33 protein resides in the cytoplasm and partially co-localizes with the caudal end of the manchette, a transient structure that guides tail elongation, in elongating spermatids, and loss of Stk33 leads to the appearance of a tight, straight and elongated manchette. Together, these results identify Stk33 as an essential regulator of spermatid differentiation and male fertility.

Place, publisher, year, edition, pages
Academic Press, 2018
Keywords
Stk33, Kinase, Spermiogenesis, Spermatogenesis, Infertility, Manchette
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-143444 (URN)10.1016/j.ydbio.2017.11.007 (DOI)000418394200008 ()29155043 (PubMedID)2-s2.0-85034594607 (Scopus ID)
Available from: 2017-12-07 Created: 2017-12-07 Last updated: 2018-09-07Bibliographically approved
Kirsch, N., Chang, L.-S., Koch, S., Glinka, A., Dolde, C., Colozza, G., . . . Niehrs, C. (2017). Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover. Developmental Cell, 43(1), 71-+
Open this publication in new window or tab >>Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover
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2017 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 43, no 1, p. 71-+Article in journal (Refereed) Published
Abstract [en]

Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation ofWnt/b-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function ofANGPTL4 invites reinterpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-142148 (URN)10.1016/j.devcel.2017.09.011 (DOI)000412557400009 ()29017031 (PubMedID)
Note

Funding Agencies|DFG [SFB 873]; HHMI

Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2018-02-06
Koch, S. (2017). Extrinsic control of Wnt signaling in the intestine. Differentiation, 97, 1-8
Open this publication in new window or tab >>Extrinsic control of Wnt signaling in the intestine
2017 (English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 97, p. 1-8Article, review/survey (Refereed) Published
Abstract [en]

The canonical Wnt/beta-catenin signaling pathway is a central regulator of development and tissue homeostasis. In the intestine, Wnt signaling is primarily known as the principal organizer of epithelial stem cell identity and proliferation. Within the last decade, numerous scientific breakthroughs have shed light on epithelial self-organization in the gut, and organoids are now routinely used to study stem cell biology and intestinal pathophysiology. The contribution of non-epithelial cells to Wnt signaling in the gut has received less attention. However, there is mounting evidence that stromal cells are a rich source of Wnt pathway activators and inhibitors, which can dynamically shape Wnt signaling to control epithelial proliferation and restitution. Elucidating the extent and mechanisms of paracrine Wnt signaling in the intestine has the potential to broaden our understanding of epithelial homeostasis, and may be of particular relevance for disorders such as inflammatory bowel diseases and colitis-associated cancers.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Cell signaling, Intestinal epithelial cells, Colon, IBD, Colorectal cancer
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-141655 (URN)10.1016/j.diff.2017.08.003 (DOI)000417863700001 ()28802143 (PubMedID)2-s2.0-85026869574 (Scopus ID)1432-0436 (Electronic) 0301-4681 (Linking) (ISBN)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2018-01-13Bibliographically approved
Berger, B. S., Acebron, S. P., Herbst, J., Koch, S. & Niehrs, C. (2017). Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP6. EMBO Reports, 18(5), 712-725
Open this publication in new window or tab >>Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP6
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2017 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 18, no 5, p. 712-725Article in journal (Refereed) Published
Abstract [en]

Wnt/beta-catenin signaling plays a key role in embryonic development, stem cell biology, and neurogenesis. However, the mechanisms of Wnt signal transmission, notably how the receptors are regulated, remain incompletely understood. Here we describe that the Parkinson's disease-associated receptor GPR37 functions in the maturation of the N-terminal bulky beta-propellers of the Wnt co-receptor LRP6. GPR37 is required for Wnt/beta-catenin signaling and protects LRP6 from ER-associated degradation via CHIP (carboxyl terminus of Hsc70-interacting protein) and the ATPase VCP GPR37 is highly expressed in neural progenitor cells (NPCs) where it is required for Wnt-dependent neurogenesis. We conclude that GPR37 is crucial for cellular protein quality control during Wnt signaling.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2017
Keywords
ER-associated degradation; GPR37; LRP6; PAEL-R; Wnt signaling
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-141651 (URN)10.15252/embr.201643585 (DOI)000400446100008 ()28341812 (PubMedID)2-s2.0-85017187389 (Scopus ID)
Note

Berger, Birgit S Acebron, Sergio P Herbst, Jessica Koch, Stefan Niehrs, Christof eng England 2017/03/28 06:00 EMBO Rep. 2017 May;18(5):712-725. doi: 10.15252/embr.201643585. Epub 2017 Mar 24.

Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2022-12-14Bibliographically approved
Koch, S., Acebron, S. P., Herbst, J., Hatiboglu, G. & Niehrs, C. (2015). Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation. Cell, 163(5), 1225-1236
Open this publication in new window or tab >>Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation
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2015 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 163, no 5, p. 1225-1236Article in journal (Refereed) Published
Abstract [en]

The canonical Wnt signaling pathway is of paramount importance in development and disease. An emergent question is whether the upstream cascade of the canonical Wnt pathway has physiologically relevant roles beyond beta-catenin-mediated transcription, which is difficult to study due to the pervasive role of this protein. Here, we show that transcriptionally silent spermatozoa respond to Wnt signals released from the epididymis and that mice mutant for the Wnt regulator Cyclin Y-like 1 are male sterile due to immotile and malformed spermatozoa. Post-transcriptional Wnt signaling impacts spermatozoa through GSK3 by (1) reducing global protein poly-ubiquitination to maintain protein homeostasis; (2) inhibiting septin 4 phosphorylation to establish a membrane diffusion barrier in the sperm tail; and (3) inhibiting protein phosphatase 1 to initiate sperm motility. The results indicate that Wnt signaling orchestrates a rich post-transcriptional sperm maturation program and invite revisiting transcription-independent Wnt signaling in somatic cells as well.

Place, publisher, year, edition, pages
Cambridge, United States: Cell Press, 2015
Keywords
Animals, Axin Protein/metabolism, Cyclins/metabolism, Epididymis/*metabolism, *Gene Expression Regulation, Glycogen Synthase Kinase 3/metabolism, Male, Mice, Phosphorylation, Protein Processing, Post-Translational, RNA Processing, Post-Transcriptional, Septins/metabolism, *Sperm Maturation, *Wnt Signaling Pathway
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-141656 (URN)10.1016/j.cell.2015.10.029 (DOI)000366044700020 ()26590424 (PubMedID)2-s2.0-84947756267 (Scopus ID)1097-4172 (Electronic) 0092-8674 (Linking) (ISBN)
Note

Koch, Stefan Acebron, Sergio P Herbst, Jessica Hatiboglu, Gencay Niehrs, Christof eng Research Support, Non-U.S. Gov't 2015/11/23 06:00 Cell. 2015 Nov 19;163(5):1225-1236. doi: 10.1016/j.cell.2015.10.029.

Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2018-01-13Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3579-4229

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