# Novel Beta-catenin Regulatory Mechanisms in C. elegans Asymmetric Cell Divisions

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $292,592

## Abstract

Asymmetric cell division (ACD) critically controls the fates of dividing stem cells during normal embryonic
development and misregulation of ACD is implicated in tumorigenesis. β-catenin, a key transcriptional effector
of Wnt signaling, is negatively regulated by a destruction complex containing casein kinase Iα (CK1α) and two
scaffolds, Axin and APC, which trigger β-catenin degradation. Wnt signaling inhibits this complex through the
Frizzled (Fz) receptor and its effector Dishevelled (Dvl), allowing β-catenin to accumulate. However, the
mechanisms that regulate the differential accumulation of β-catenin after ACD are unclear in any system.
Elucidating these mechanisms would provide broadly important insight into cell fate specification. Our objective
is to determine the mechanisms of β-catenin regulation during ACD. C. elegans exhibits Wnt-regulated
asymmetric stem cell divisions where only one of the daughter cells activates Wnt target genes. These ACDs
thus provide an ideally powerful experimental model for understanding Wnt signaling in an intact organism. We
have found that the C. elegans β-catenin, SYS-1, is regulated by an ortholog of the vertebrate destruction
complex component, APR-1/APC, which asymmetrically localizes to one pole of the dividing cell and control
asymmetric SYS-1 levels after ACD. We will test the central hypothesis that, because tight control of SYS-1
regulation is required, multiple SYS-1 negative regulatory mechanisms are needed in ACD. Supporting this, we
have shown that PRY-1/Axin is required to establish the site of SYS-1 destruction by localizing APR-1/APC.
We have also shown that SYS-1 is negatively regulated by localization to mother cell centrosomes during
ACD. Our data also implicate an asymmetric nuclear export mechanism in the unsignaled daughter. We
propose to: Aim 1. Determine the mechanism by which asymmetric PRY-1/Axin activity is achieved. To test our
hypothesis that Wnt ligands activate a Fz/Dvl-based PRY-1 polarization mechanism, we will: A) determine the
location of the functional destruction complex during normal ACD and after optogenetically inducing Wnt
expression to alter mother cell polarity, B) examine the ability of Dvl to generate “signalosomes” and inactivate
the destruction complex and C) identify the protein interactions that lead to asymmetric PRY-1/Axin activity.
Aim 2. Determine the mechanism of centrosomal control of SYS-1-dependent cell fate. To test our hypothesis
that mother cell SYS-1 localizes to the centrosome and is degraded during ACD, we will A) conduct pulse-
chase assays using a photoconvertible SYS-1 to examine centrosomal SYS-1 inheritance, B) genetically place
centrosomal regulators in the Wnt pathway, C) examine the whether centrosomal SYS-1 regulation is
microtubule-dependent and D) extend our analyses to human β-catenin. Aim 3. Determine the role of nuclear
export in asymmetric SYS-1 nuclear accumulation. To test the hypothesis that asymmetric SYS-1 nuclear
export occ...

## Key facts

- **NIH application ID:** 9994750
- **Project number:** 5R01GM114007-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** BRYAN T PHILLIPS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $292,592
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994750

## Citation

> US National Institutes of Health, RePORTER application 9994750, Novel Beta-catenin Regulatory Mechanisms in C. elegans Asymmetric Cell Divisions (5R01GM114007-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9994750. Licensed CC0.

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