# Molecular Mechanisms of Regeneration Termination

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $326,072

## Abstract

Project Summary
 The molecular mechanisms by which stem cell proliferation is precisely controlled during the course
of regeneration are poorly understood. Namely, how a damaged tissue senses when to terminate the
regeneration process, inactivates stem cell mitotic activity, and organizes ECM integrity remain fundamental
unanswered questions. Uncontrolled proliferation of stem cells in regenerative tissues can result in tumor
formation. The Drosophila midgut intestinal stem cell (ISC) has recently emerged as an attractive model
system to study tissue homeostasis and regeneration. This is due to striking similarities in genetic control
and cellular composition between the Drosophila and mammalian digestive systems, and powerful genetic
tools available in this model. Importantly, Drosophila ISC proliferation is promoted in response to tissue
damage to stimulate tissue repair. Using this model system, a number of studies have been conducted to
reveal the pathways that activate ISC proliferation.
 Despite a wealth of knowledge on the activation of proliferative capacity of stem cells, it is largely
unknown how the tissue properly down-regulates stem cell proliferation at the end of regeneration and how
this process is linked to epithelial remodeling. We recently established the Drosophila ISCs as an excellent
model to study the molecular basis for regeneration termination. Using RNA-seq, we identified sets of
genes and pathways that are up/down-regulated at different phases of regeneration. Among these, we
found that dMOV10, a component of the microRNA (miRNA) gene silencing complex, is required for the
proper termination of the regeneration process. Further analyses identified direct target mRNAs of
dMOV10-containing miRISC, including baboon (the Type I receptor of activin signaling) and two major non-
integrin ECM receptors, Syndecan (a transmembrane heparan sulfate proteoglycan) and Dystroglycan (an
integral membrane component of the dystrophin-glycoprotein complex). In addition to the identification of
dMOV10 as a termination stage-specific gene, this same RNA-seq analysis showed that key components
for septate junctions, and actin regulators are specifically upregulated during regeneration and return to
normal level at a late stage.
 In this proposal, we will define these key molecules in stem cell inactivation and ECM remodeling at
the termination stage of Drosophila midgut regeneration through the following Specific Aims. Aim 1.
Determine the role of septate junction components in midgut regeneration. Aim 2. Define the role of Sdc
and Dg in ECM remodeling. Aim 3. Define the global landscape of the miRNA-mediated network.

## Key facts

- **NIH application ID:** 10757602
- **Project number:** 5R01HD108059-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Hiroshi Nakato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $326,072
- **Award type:** 5
- **Project period:** 2022-03-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757602

## Citation

> US National Institutes of Health, RePORTER application 10757602, Molecular Mechanisms of Regeneration Termination (5R01HD108059-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757602. Licensed CC0.

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