Digitala Vetenskapliga Arkivet

Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The POU/Oct Transcription Factor Nubbin Controls the Balance of Intestinal Stem Cell Maintenance and Differentiation by Isoform-Specific Regulation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0001-9875-8829
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2018 (English)In: Stem Cell Reports, ISSN 2213-6711, Vol. 10, no 5, p. 1565-1578Article in journal (Refereed) Published
Abstract [en]

Drosophila POU/Oct transcription factors are required for many developmental processes, but their putative regulation of adult stem cell activity has not been investigated. Here, we show that Nubbin (Nub)/Pdm1, homologous to mammalian OCT1/POU2F1 and related to OCT4/POU5F1, is expressed in gut epithelium progenitor cells. We demonstrate that the nub-encoded protein isoforms, Nub-PB and Nub-PD, play opposite roles in the regulation of intestinal stem cell (ISC) maintenance and differentiation. Depletion of Nub-PB in progenitor cells increased ISC proliferation by derepression of escargot expression. Conversely, loss of Nub-PD reduced ISC proliferation, suggesting that this isoform is necessary for ISC maintenance, analogous to mammalian OCT4/POU5F1 functions. Furthermore, Nub-PB is required in enteroblasts to promote differentiation, and it acts as a tumor suppressor of Notch RNAi-driven hyperplasia. We suggest that a dynamic and well-tuned expression of Nub isoforms in progenitor cells is required for maintaining gut epithelium homeostasis.

Place, publisher, year, edition, pages
2018. Vol. 10, no 5, p. 1565-1578
Keywords [en]
Pdm1, POU, homeodomain, Drosophila, stem cell, epithelium regeneration, Escargot, Notch, mitosis, midbody
National Category
Developmental Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-155389DOI: 10.1016/j.stemcr.2018.03.014ISI: 000432931400015OAI: oai:DiVA.org:su-155389DiVA, id: diva2:1199197
Available from: 2018-04-19 Created: 2018-04-19 Last updated: 2018-06-25Bibliographically approved
In thesis
1. Isoform-specific regulation of Drosophila gut immunity and regeneration by the POU/Oct transcription factor Nub/Pdm1
Open this publication in new window or tab >>Isoform-specific regulation of Drosophila gut immunity and regeneration by the POU/Oct transcription factor Nub/Pdm1
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Innate immune reactions protect organisms against a variety of infections.  In metazoans, these reactions involve both cellular and humoral responses. The immune responses have to be well-tuned, as excessive immune activation is associated with tissue-specific pathologies. However, the transcriptional regulatory mechanisms underlying how immune responses are balanced are still not well understood. The aim of this study was to investigate the role of the Drosophila POU/Oct transcription factor Nubbin (Nub) in regulating Drosophila innate immunity, with a special focus on intestinal immune and epithelium homeostasis.

In Paper I, we show that the nub gene encodes two independent transcription factor isoforms, Nub-PB and Nub-PD. The short isoform, Nub-PD, acts as a repressor of NF-κB/Relish-dependent antimicrobial peptide (AMP) gene expression in healthy flies. Furthermore, we demonstrate that Nub-PD directly binds to Oct sequence motifs located in the distal promoter region of several AMP genes, thereby inhibiting gene transcription. In addition, loss of Nub-PD diminishes the number of cultivatable gut bacteria, possibly due to high expression levels of AMP genes. In Paper II, we show that the large isoform, Nub-PB, in a sharp contrast to Nub-PD, activates AMP gene expression, both independently of and together with Relish. Importantly, Nub-PB and Nub-PD regulated the same target AMP gene expression antagonistically. In addition, Nub-PB expression in gut enterocytes (ECs) negatively correlated with gut microbial loads and host lifespan. Finally, we found that enforced Nub-PB expression in ECs promotes a pro-inflammatory signature and stimulated epithelium renewal. In Paper III, we show that Nub-PB and Nub-PD are not only expressed in differentiated gut ECs, but also present in midgut progenitor cells. Depletion of Nub-PB in gut progenitor cells results in hyperproliferation of intestinal stem cells (ISCs), via direct or indirect de-repression of Escargot expression. Furthermore, enforced Nub-PB expression in ISCs and enteroblasts (EBs) inhibited Notch RNAi-induced tumor formation. In addition, Nub-PD was necessary for both basal and infection-induced ISC proliferation. Strikingly, Nub-PB and Nub-PD regulated ISC proliferation in antagonistic manners. In Paper IV, we created a Nub-PB-specific mutant and found that this mutant impairs normal gut development, giving rise to short and wide anterior midguts. Furthermore, loss of Nub-PB promoted rapid ISC proliferation, increased EC delamination, and increased numbers of enteroendocrine cells in the anterior midgut.

Taken together, we have characterized a novel isoform-specific regulatory mechanism, involved in maintaining Drosophila intestinal immune homeostasis and epithelial regeneration. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2018. p. 62
Keywords
POU, Nubbin, Drosophila, intestinal stem cell, epithelium regeneration, midgut, mitosis, Antimicrobial peptides, innate immunity, NF-κB, bacterial infection, transcriptional regulation, homeostasis
National Category
Biological Sciences
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-155393 (URN)978-91-7797-276-1 (ISBN)978-91-7797-277-8 (ISBN)
Public defence
2018-06-07, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrehnius väg 20, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2018-05-15 Created: 2018-04-19 Last updated: 2020-05-08Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full text

Search in DiVA

By author/editor
Tang, XiongzhuoZhao, YunpoEngström, Ylva
By organisation
Department of Molecular Biosciences, The Wenner-Gren Institute
In the same journal
Stem Cell Reports
Developmental Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 307 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf