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DOI | 10.1126/science.aba4517 |
Mapping the molecular and cellular complexity of cortical malformations | |
Esther Klingler; Fiona Francis; Denis Jabaudon; Silvia Cappello | |
2021-01-22 | |
发表期刊 | Science
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出版年 | 2021 |
英文摘要 | When brain development goes awry, whether in genes or cells or circuits, neurodevelopmental disorders ensue. Klingler et al. review how disrupted development leads to clinical symptoms, with a particular focus on the linkage between cortical malformations and neuropsychiatric disorders. The complexity of the developmental process may underlie the variability in symptoms.
Science , this issue p. [eaba4517][1]
### INTRODUCTION
The cerebral cortex, or neocortex, is critical to key mammalian skills such as language, sociability, and sensorimotor control. This structure consists of dozens of specialized types of neurons organized across layers and areas, which are generated during development by diverse types of progenitors. Newborn neurons then undergo sequential molecular programs that drive their specific local and long-range circuit connectivity and adult function. Although they are necessary for proper cortical function to emerge, these myriads of molecular and cellular developmental processes provide multiple points of vulnerability for “cortical malformations,” which cause various combinations of intellectual and/or motor disabilities that are often associated with seizures. These disabilities include microcephaly (decreased brain size), lissencephaly (loss of cortical folding), polymicrogyria (numerous small cortical folds), dysplasia (abnormal cortical lamination, which can be focal), and heterotopias (abnormally positioned cells in periventricular or subcortical regions). Despite the toll on patients and their caregivers, only limited treatments exist and although some causal genes have been identified, the sequence of events linking molecular disruption with clinical expression mostly remains obscure.
### RATIONALE
To better understand cortical malformations and to highlight potential points of intervention, we first present basic principles of neocortical development and point out vulnerable cellular compartments and processes. Second, we dissect different “levels” of organization, from genes to cells, circuits, and clinical expression, and illustrate how complex interactions within and across these levels may account for variable disease patterns in cortical malformations. We finally propose a framework integrating these different levels of organization to assist in better understanding and treating such diseases.
### RESULTS
We first present basic principles of neocortical development that result from billions of cells undergoing four key sequential and partially overlapping processes: (i) progenitor division and neurogenesis, (ii) neuron migration, (iii) extension of axon and dendrites, and (iv) synaptogenesis. We point out vulnerable cellular compartments and processes, with particular focus on neurogenesis and neuron migration, and highlight potential sources of variability that have precluded the establishment of clear causal relationships across genes and molecules, cell types, circuits, and clinical expression. Starting with genetic and molecular dysfunction, we examine monogenic versus polygenic causes of disease and their convergent (i.e., mutations in distinct genes leading to the same phenotype), divergent (i.e., mutations in a single gene leading to distinct phenotypes), or mixed relationships with disease phenotype(s). The contribution of redundant molecular mechanisms and versatility in protein function to the variability of disease processes is discussed and illustrated by examples. Disrupted spatiotemporal expression of genes, cell type–specific defects, and relationships between cell position and circuit wiring are also covered. Finally, we argue that comparison of gene expression across brain development in different animal models (including mouse and monkey), in humans, and in human-derived brain organoids is particularly important to identify affected processes. As a step in this direction, we provide an online resource ( |
领域 | 气候变化 ; 资源环境 |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/312361 |
专题 | 气候变化 资源环境科学 |
推荐引用方式 GB/T 7714 | Esther Klingler,Fiona Francis,Denis Jabaudon,et al. Mapping the molecular and cellular complexity of cortical malformations[J]. Science,2021. |
APA | Esther Klingler,Fiona Francis,Denis Jabaudon,&Silvia Cappello.(2021).Mapping the molecular and cellular complexity of cortical malformations.Science. |
MLA | Esther Klingler,et al."Mapping the molecular and cellular complexity of cortical malformations".Science (2021). |
条目包含的文件 | 条目无相关文件。 |
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