# Regulating cell fate and shaping the body plan during morphogenesis and their alteration during oncogenesis

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $595,169

## Abstract

7. Abstract
One of biology’s central challenges to define the mechanisms by which the single cell zygote assembles itself
into the complex body plan of an animal. For the last 27 years we have addressed this fundamental question,
following the lead initially provided by the dual functions of bcatenin in cell adhesion and Wnt signaling. We
seek to determine how cells assemble polarized tissues and organs and change shape and move during
morphogenesis, by coordinating cell adhesion and the cytoskeleton. In parallel, we study Wnt signaling, a
paradigm for mechanisms cells use to choose and maintain fate in development and homeostasis and how this
goes wrong in disease. We study these events in Drosophila, using its sophisticated genetic tools along with
cutting edge microscopy to explore events in vivo, and combine this with work in cultured mammalian cells, to
explore conservation and divergence of these mechanisms. Many of the proteins on which we focus are
disrupted in human developmental disorders, cancer initiation and metastasis. Currently we explore three key
questions in the field. First, we ask how cells initiate and maintain apical-basal polarity, a fundamental property
of animal tissues. Cell-cell adherens junctions serve as key polarity landmarks, demarcating the apical and
basolateral domains. Our goal is to determine how different upstream inputs are integrated to position
adherens junctions during apical-basal polarity establishment, and to define mechanisms ensuring robust
polarity maintenance. We hypothesize that the egg plasma membrane and the polarized cytoskeleton it
organizes act through multiple effectors to position adherens junctions, with junctional proteins acting as
coincidence detectors, and that new mechanisms turn on at gastrulation onset, buffering errors during
cellularization. Second, we explore mechanisms by which cell-cell junctions link to the actomyosin cytoskeleton
to allow cell shape change without disrupting epithelial integrity. We hypothesize different cells choose from an
array of proteins/protein complexes to assemble and link adherens junctions, with different proteins
contributing distinct dynamics or force resistance, and that multivalent interactions among the proteins
increases robustness. In parallel, we ask how upstream signaling cues drive integrated cytoskeletal responses
in morphogenesis, using Abl kinase as a model. Third, we explore how cells choose and maintain fate, using
Wnt signaling as a model. We focus on the tumor suppressor Adenomatous polyposis coli (APC), a key
negative regulator that is mutated in 80% of colon cancers. Our long-term goal is to determine how APC and
its partners in the Wnt-regulatory destruction complex regulate signaling during development and homeostasis,
and how that goes wrong in cancer. We hypothesize that the destruction complex is a multimeric machine
assembled by polyvalent interactions, that its cellular localization and assembly state are regulated by Wnt
si...

## Key facts

- **NIH application ID:** 10458458
- **Project number:** 5R35GM118096-07
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Mark A. Peifer
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $595,169
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458458

## Citation

> US National Institutes of Health, RePORTER application 10458458, Regulating cell fate and shaping the body plan during morphogenesis and their alteration during oncogenesis (5R35GM118096-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458458. Licensed CC0.

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