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23. Cellular and Molecular Analysis of Axon Development in Zebrafish

Author

Xing, Lingyan

Subjects
nervous system
Abstract

Brain wiring is critical for normal brain function, and brain connection defects have been described in many neurodevelopmental disorders. Accurate central nervous system connectivity relies on precise axon navigation. The cellular and molecular mechanisms governing axon guidance during development are important but not well understood. In this dissertation, I utilize zebrafish, a powerful vertebrate model in developmental and genetic studies, to determine the molecular mechanisms regulating axon guidance in vivo. We specifically determine the role of the two molecules FoxP2 and serotonin (5-HT) in axon guidance. We demonstrate that FoxP2, a forkhead-domain transcription factor, is not required for axon guidance, but it reduces the expression levels of a synaptic protein Cntnap2. We also establish that 5-HT and its receptor Htr2a are important for axon guidance. The regulation of 5-HT on axon guidance is mediated by the tyrosine kinase Ephrinb2a. Moreover, we discover that axon guidance defects induced by environmental hypoxia can be rescued by serotonin reuptake inhibitor fluoxetine. I have also developed and implemented a PCR-based high resolution melting analysis (HRMA) for large-scale genotype screening and characterization of genes involved in axon development. Taken together, this work identifies a novel mechanism involved in central nervous system connectivity, and indicates raphe 5-HT neurons act as a sensor to alterations in the developmental environment.

Published
2016
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25. Developmental dopaminergic signaling modulates neural circuit formation and contributes to autism spectrum disorder (ASD)-related phenotypes

Author

Lu, Xiaojuan, Song, Yixing, Wang, Jiaqi, Cai, Yunyun, Peng, Siwan, Lin, Jiaqi, Lai, Biqin, Sun, Junjie, Liu, Tianqing, Chen, Gang, and Xing, Lingyan

Abstract

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with a complex etiology. Recent evidence suggests that dopamine plays a crucial role in neural development. However, it remains unclear whether and how disrupted dopaminergic signaling during development contributes to ASD. In this study, human brain RNA-seq transcriptome analysis revealed a significant correlation between changes in dopaminergic signaling pathways and neural developmental signaling in ASD patients. In the zebrafish model, disrupted developmental dopaminergic signaling led to neural circuit abnormalities and behavior reminiscent of autism. Dopaminergic signaling may impact neuronal specification by potentially modulating integrins. These findings shed light on the mechanisms underlying the link between disrupted developmental dopamine signaling and ASD, and they point to the possibility of targeting dopaminergic signaling in early development for ASD treatment.

Published
2024
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30. New evidence of vascular defects in neurodegenerative diseases revealed by single cell RNA sequencing.

Author

Qiu J, Peng S, Qu R, Wu L, Xing L, Zhang L, and Sun J

Subjects
Humans, Animals, Brain pathology, Brain blood supply, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Single-Cell Analysis methods, Sequence Analysis, RNA methods
Abstract

Neurodegenerative diseases (NDs) involve the progressive loss of neuronal structure or function in the brain and spinal cord. Despite their diverse etiologies, NDs manifest similar pathologies. Emerging research identifies vascular defects as a previously neglected hallmark of NDs. The development and popularization of single-cell RNA sequencing (scRNA-seq) technologies have significantly advanced our understanding of brain vascular cell types and their molecular characteristics, including gene expression changes at the single-cell level in NDs. These unprecedented insights deepen our understanding of the pathogenic mechanisms underlying NDs. However, the occurrence and role of vascular defects in disease progression remain largely unexplored. In this paper, we systematically summarize recent advances in the structure and organization of the central nervous system vasculature in mice, healthy individuals, and patients with NDs, focussing primarily on disease-specific alterations in vascular cell types or subtypes. Combining scRNA-seq with pathology evidence, we propose that vascular defects, characterized by disruptions in cell types and structural integrity, may serve as common early features of NDs. Finally, we discuss several pathways through which vascular defects in NDs lead to neuronal degeneration. A deeper understanding of the causes and contributions of vascular defects to NDs aids in elucidating the pathogenic mechanisms and developing meaningful therapeutic interventions., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Published
2024
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