# Surface ectodermal mechanism and maternal intervention of neural tube defects

> **NIH NIH R01** · ADA FORSYTH INSTITUTE, INC. · 2022 · $341,953

## Abstract

PROJECT SUMMARY/ABSTRACT
 Neural tube closure defects (NTDs) are among the commonest and severest birth defects. The long-term
goal of our research is to uncover the cellular and molecular mechanisms of mammalian NTDs. Understanding
the basic mechanisms underlying neural tube closure may translate into applications for preventing NTDs,
including exencephaly and anencephaly at the cranial region and spina bifida at the caudal spinal region.
Craniorachischisis, the severest but rare NTD with an entirely open brain and spine, has been found in the
animal model of planar cell polarity (PCP) signaling mutants. The Wnt/ß-catenin signaling pathway shares a
few components with the PCP signaling pathway, and plays crucial roles in a wide range of developmental
processes and related disorders. However, the role of Wnt/ß-catenin signaling in neural tube closure and NTDs
remains poorly understood. Lrp6 is a coreceptor in the Wnt/ß-catenin signaling pathway and is also involved in
the PCP signaling pathway with unknown mechanisms. Spontaneous point mutations in the Lrp6 gene give
rise to either cranial or spinal NTDs in the mouse model, and are associated with NTDs in humans. Folate
supplementation may not prevent NTDs in Lrp6 mutants. To address the role of Lrp6-mediated signaling
cascades in neural tube closure, we generated a conditional gene-targeting mouse line of Lrp6. Using various
Cre mouse lines, we preliminarily found that Lrp6 plays cell lineage- and region-specific roles in neural tube
closure. Moreover, Lrp6 may have functional redundancy with another coreceptor, Lrp5, in mediating ß-catenin
signaling during neural tube closure. We recently demonstrated that conditional ablation of ß-catenin in the
neuroectodermal lineage cells causes spina bifida that is similar to, but severer than those seen in the
neuroectodermal Lrp6 mutants, suggesting that Lrp5 may partially compensate for loss-of-function of Lrp6 in
mediating Wnt/ß-catenin signaling. Numerous studies have focused on the neuroectoderm or neuroepithelium
that is important in neural plate folding or bending during neural tube closure. However, the role of the adjacent
non-neural surface ectoderm during neural tube closure remains poorly understood. Based on our significant
preliminary findings, we propose that Lrp6/Lrp5-mediated ß-catenin signaling regulates a unique cellular
process in the non-neural surface ectodermal cells to direct neural tube closure along the entire rostrocaudal
body axis, and that disruption of the Lrp/ß-catenin signaling cascade in the non-neural surface ectodermal cells
will cause a spectrum of all types of severe NTDs. We also propose that genetic activation of the downstream
effectors or pharmacological activation of Wnt/ß-catenin signaling can prevent NTDs in the surface ectodermal
mutants. To address these hypotheses, Specific Aim 1 will conduct conditional gene-targeting analyses in
combination with various powerful and innovative research approaches to examine...

## Key facts

- **NIH application ID:** 11078102
- **Project number:** 7R01NS102261-06
- **Recipient organization:** ADA FORSYTH INSTITUTE, INC.
- **Principal Investigator:** Chengji Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $341,953
- **Award type:** 7
- **Project period:** 2024-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11078102

## Citation

> US National Institutes of Health, RePORTER application 11078102, Surface ectodermal mechanism and maternal intervention of neural tube defects (7R01NS102261-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11078102. Licensed CC0.

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