# The Wnt-independent role of TCF7l2 in CNS myelin formation and repair

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $343,438

## Abstract

Oligodendrocytes (OLs) are myelin-forming cells in the central nervous system (CNS). CNS myelin
formation/repair consists of two closely-related sequential events: OL differentiation from oligodendrocyte
progenitor cells and axonal (re)myelination by already differentiated OLs. Defects of these two events result in
abnormalities of CNS myelin formation such as in periventricular leukomalacia and inability of myelin repair
such as in multiple sclerosis. Our long term goal is to study the underlying mechanisms regulating CNS myelin
formation/repair. The expression of the Wnt effector transcription factor 7-like 2 (TCF7l2, a.k.a. TCF4) in
multiple sclerosis lesions is one such promising mechanism.
 A well-studied role of TCF7l2 is transcriptionally mediating Wnt/β-catenin signaling in Wnt activated
cells such as colorectal cancer cells. Previous studies from others and our own laboratory have shown that
genetic activation of canonical Wnt/β-catenin signaling pathway inhibits OL differentiation (review Guo et al.,
2015).Therefore, it has been proposed that TCF7l2 inhibits OL differentiation acting through Wnt/β-catenin
signaling. However, we recently reported that conditionally disrupting TCF7l2 by Cre-loxP genetic approach
inhibits neonatal and early postnatal OL differentiation without perturbing Wnt/β-catenin signaling pathway
(Hammond et al., 2015). Based on our genetic data, we propose an alternative hypothesis that TCF7l2, acting
through non-Wnt pathways (Aim 2), is a multimodal positive regulator of CNS myelin formation (Aim 1) that
can be manipulated to promote CNS myelin repair after myelin damage (Aim 3).
 In Aim 1, we will specifically ablate TCF7l2 in already differentiated OLs to determine its role in
subsequent axonal myelination and myelin lipid synthesis. The experiments in this Aim will reveal a previously
unrecognized novel role of TCF7l2 in CNS myelination independent of upstream OL differentiation. In Aim 2,
we will use in vivo and in vitro genetic approaches to test the hypothesis that TCF7l2's function as a gene
repressor plays an essential role in CNS myelin formation. This project will unveil a novel link between TCF7l2
and an oligodendroglial autocrine pathway that inhibits OL differentiation and myelination. Our paradigm-
shifting data make it necessary and important to revisit and reevaluate the therapeutic potential of TCF7l2
during CNS myelin repair which has been proposed as an inhibitory factor in human multiple sclerosis. In Aim
3, we will use lentiviral vector-mediated gene transfer to test the alternative hypothesis that enforced TCF7l2
expression promotes OL differentiation and CNS myelination in demyelination animal models. The expected
overall impact of this innovative proposal is that it will fundamentally advance our mechanistic understanding
of CNS myelin formation and of novel role of TCF7l2, and will change our conventional view of inhibiting
TCF7l2 to enhance CNS myelin repair.

## Key facts

- **NIH application ID:** 9981843
- **Project number:** 5R01NS094559-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Fuzheng Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,438
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981843

## Citation

> US National Institutes of Health, RePORTER application 9981843, The Wnt-independent role of TCF7l2 in CNS myelin formation and repair (5R01NS094559-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981843. Licensed CC0.

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