Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY/ABSTRACT Neural tube closure defects (NTDs) are among the most common and severe birth defects. The long-term goal of our research is to uncover the fundamental mechanisms of mammalian NTDs, which may translate into applications for preventing NTDs. The most common and significant type of NTDs is spina bifida that occurs when the spinal column does not close completely and spinal cord and/or spinal meninges may protrude through the back. Newborns with spina bifida are viable but usually have impaired bladder and bowel functions and paralysis of the lower limbs, which result in serious long-term morbidity and disabilities, and even early death. The research targeted at the cause and intervention of NTDs, particularly, spina bifida in this project is thus highly significant. The genetically modified mutant mouse models have provided significant clues of human NTDs. Among hundreds of NTD-associated genes, Wnt family genes play key roles in neural tube closure and abnormal Wnt signaling may cause folate-resistant NTDs in both animal models and humans. Craniorachischisis, the severest but rare NTD with an entirely open brain and spine, has been found in the animal models of the non-canonical Wnt/planar cell polarity (PCP) signaling mutants. The canonical Wnt/ß-catenin signaling pathway shares several components with the PCP signaling pathway and plays crucial roles in a wide range of developmental processes and related disorders. Our published works demonstrate indispensable roles of Wnt/ß-catenin signaling in neural tube closure and spinal NTDs. At the cellular level, we recently revealed previously understudied non-neural surface ectodermal cells which form the multi-cellular rosette structures, convergent cellular protrusions, and a unique F-actin cable network at the leading fusion site during neural tube closure. These unique surface ectodermal structures are severely disrupted in the surface ectodermal mutant mice with fully penetrant spinal NTDs. This project is designed to systematically address the transcriptomic landscapes and gene-regulatory networks in the surface ectodermal cells during normal and defective neural tube closure using unbiased single-cell transcriptomics in combination with conditional gene-targeting approaches of the integrated Wnt signaling and PCP signaling, which may reveal novel mechanisms underlying spinal NTDs and provide a basis for developing novel strategies to prevent folate-untreatable NTDs in human newborns through transcriptomic modulations of the key gene-regulatory networks.
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