# CryoEM studies of Wnt3a-FZD8-LRP6 signaling complex in neurogenesis and regeneration

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA LINCOLN · 2024 · $199,468

## Abstract

Wnt signaling is crucial both for neuronal neurogenesis and for synaptic plasticity and maintenance in the 
adult brain. Thus, modulating Wnt-mediated neurogenesis and regeneration represents a promising 
treatment for both central nervous system injuries and neurodegenerative diseases like Parkinson’s and 
Alzheimer’s. The canonical Wnt3a signaling pathway plays fundamental role in the medically relevant 
neurogenesis and regeneration and stem-cell renewal. The central event of the Wnt3a pathway is the 
formation of Wnt3a-FZD8-LRP6 transmembrane complex, which initiates and transduces the signal from 
the extracellular side into the intracellular side of the cell membrane. The lack of structural information on 
the intact Wnt3a-FZD8-LRP6 signaling complex or any other complex structure of their homologs greatly 
hinders our understanding of molecular mechanisms for this fundamental pathway and impairs the 
development of Wnt-related regenerative therapeutics. The central goal of this research is to determine the 
structure-based mechanisms of the canonical Wnt3a-FZD8-LRP6 complex by single particle cryo-EM. The 
structural study will allow us to visualize the atomic interactions between the Wnt3a ligand and its receptors 
FZD8 and LRP6, map key structural elements that are responsible for signal transduction, and identify 
potential locations for future therapeutic molecule development. We will also study the structure of the 
Wnt3a-FZD8-LRP6 complex that purified from native source and investigate the basis of Wnt ligand 
selectivity and specificity which is a great puzzle in the field considering there are multiple Wnt ligands and 
receptors. Additionally, we will apply time-resolved cryo-EM studies to resolve the signal transduction 
dynamics and visualize the Wnt3a signal transduction in near real time. The results of this research 
program will not only serve as a foundation for understanding the molecular principles by which other Wnt 
ligands induce signal transduction and related pathological mechanisms in multiple types of diseases 
including cancer, but also pave the way for the rational design of next-generation therapies for 
degenerative diseases and injuries.

## Key facts

- **NIH application ID:** 10914320
- **Project number:** 5P20GM113126-09
- **Recipient organization:** UNIVERSITY OF NEBRASKA LINCOLN
- **Principal Investigator:** Yihe Huang
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $199,468
- **Award type:** 5
- **Project period:** 2016-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914320

## Citation

> US National Institutes of Health, RePORTER application 10914320, CryoEM studies of Wnt3a-FZD8-LRP6 signaling complex in neurogenesis and regeneration (5P20GM113126-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10914320. Licensed CC0.

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