Thursday, November 21, 2024
11/21/2024
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 the cellular and molecular mechanisms of NTDs in the surface ectodermal Lrp6 mutants. Specific Aim 2 will address genetic interaction or gene-dosage-dependent roles of Lrp5, Lrp6, and ß-catenin signaling during neural tube closure. Specific Aim 3 will test rescue or prevention of NTDs by conditional activation of the key candidate downstream effectors or maternal supplementation of small-molecule nutrients. This study may reveal significant clues toward developing novel strategies to prevent folate-untreatable NTDs in human newborns.
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