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Characterization of the role of Nub-PB in gut epithelium regeneration
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.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The gene for Drosophila POU/Oct transcription factor Nubbin (Nub)/Pdm1 encodes two independent isoforms, Nub-PB and Nub-PD, which act antagonistically in gut progenitor cells to maintain normal intestinal stem cell (ISC) proliferation. However, the role of Nub-PB in regulating midgut epithelium regeneration is not fully understood.  Here, we have created a viable nub mutant named nubPB-3 and find that this mutant displays shortened adult lifespan in normal rearing conditions. Careful analysis of nubPB-3 midgut morphology revealed an enlarged anterior midgut with increased ISC proliferation, enhanced enteroendocrine (EE) lineage differentiation and enforced delamination of enterocytes (ECs). Furthermore, we found that the increased ISC proliferation in the nubPB-3 mutant is caused by the high activity of JAK/STAT signaling in the anterior midgut, indicating that Nub-PB normally represses the JAK/STAT activity in progenitor cells. A high rate of ISC proliferation caused by oral Ecc15 infection was, however, not dependent on Nub-PB.  This suggests a role for Nub-PB in suppressing the rate of ISC proliferation under normal conditions, a role which is lost during infection-induced proliferation. Interestingly, nubPB-3 mutants were susceptible to Ecc15 infection and died shortly thereafter. While this was not due to gut epithelium leakage or impaired antimicrobial peptide gene expression, a more general failure in gut physiology, digestion and metabolism may be the underlying cause of death.

National Category
Developmental Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-155386OAI: oai:DiVA.org:su-155386DiVA, id: diva2:1199076
Available from: 2018-04-19 Created: 2018-04-19 Last updated: 2018-04-23Bibliographically 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
Keyword
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: 2018-05-15Bibliographically approved

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