From development to disease 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 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 (http://www.humous.org) compiling transcriptional maps across embryonic development and neuron differentiation for mouse embryos, human embryos, and human brain organoids. CONCLUSION Using select examples, we highlight several levels (i.e., genetic, molecular, cellular, circuit, and behavioral) within and across which combinatorial interactions occur during cortical malformations and which hamper a causal understanding of the disease process. Discerning the processes involved at each of these levels for individual patients is key to providing them and their families with prognostic indicators and therapeutic perspectives. Integrative approaches including electrophysiological, imaging, clinical, and biological data in patients using state-of-the art artificial intelligence algorithms may allow bridging DNA mutation(s) to molecular, cellular, anatomical, and circuit features. This will be instrumental for the physiopathogenic classification of diseases, which is an essential step in patient stratification and in the design of personalized diagnostic and therapeutic tools. Emergence of complexity in cortical malformations. Shown are levels of organization during corticogenesis, from genes to gene expression (RNA and proteins), cells, circuits and anatomy, and phenotype. Each circle represents a given feature of that level. Interactions within levels are linked through complex relationships to states at other levels. Examples of abnormal linear (brandy red), convergent (cyan), and divergent (blue) feature relationships across levels in disease are highlighted. The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.

中文翻译：

---

绘制皮质畸形的分子和细胞复杂性

从发育到疾病 当大脑发育出现问题时，无论是基因、细胞还是回路，都会导致神经发育障碍。克林勒等人。回顾发育障碍如何导致临床症状，特别关注皮质畸形和神经精神疾病之间的联系。发育过程的复杂性可能是症状变异性的基础。科学，这个问题 p。eaba4517 介绍 大脑皮层或新皮层对关键的哺乳动物技能（如语言、社交能力和感觉运动控制）至关重要。这种结构由跨层和区域组织的数十种特殊类型的神经元组成，这些神经元在发育过程中由不同类型的祖细胞生成。然后新生神经元经历顺序分子程序，驱动它们特定的局部和远程电路连接和成人功能。尽管它们对于正常皮质功能的出现是必要的，但这些无数的分子和细胞发育过程为“皮质畸形”提供了多个脆弱点，这会导致通常与癫痫发作相关的智力和/或运动障碍的各种组合。这些残疾包括小头畸形（大脑尺寸减小）、无脑畸形（皮质折叠丧失）、多小脑回（大量小皮质折叠）、发育不良（皮质分层异常，可能是局灶性的）和异位（脑室周围或皮质下区域的细胞位置异常） . 尽管对患者及其护理人员造成了损失，仅存在有限的治疗方法，尽管已经确定了一些因果基因，但将分子破坏与临床表达联系起来的事件序列大多仍不清楚。基本原理为了更好地了解皮层畸形并突出潜在的干预点，我们首先介绍新皮层发育的基本原理并指出脆弱的细胞区室和过程。其次，我们剖析了组织的不同“层次”，从基因到细胞、回路和临床表达，并说明这些层次内部和之间的复杂相互作用如何解释皮质畸形中的可变疾病模式。我们最终提出了一个整合这些不同组织层次的框架，以帮助更好地理解和治疗这些疾病。结果我们首先介绍了由数十亿个细胞经历四个关键的连续和部分重叠过程产生的新皮质发育的基本原理：（i）祖细胞分裂和神经发生，（ii）神经元迁移，（iii）轴突和树突的延伸，以及（iv） ) 突触发生。我们指出了脆弱的细胞区室和过程，特别关注神经发生和神经元迁移，并强调了潜在的变异来源，这些来源阻止了跨基因和分子、细胞类型、回路和临床表达建立明确的因果关系。从遗传和分子功能障碍开始，我们检查了疾病的单基因与多基因原因及其收敛性（即导致相同表型的不同基因的突变）、发散性（即，导致不同表型的单个基因中的突变），或与疾病表型的混合关系。通过例子讨论和说明了蛋白质功能的冗余分子机制和多功能性对疾病过程变异性的贡献。基因的时空表达中断、细胞类型特异性缺陷以及细胞位置和电路布线之间的关系也包括在内。最后，我们认为在不同动物模型（包括小鼠和猴子）、人类和人源大脑类器官中比较大脑发育的基因表达对于识别受影响的过程尤为重要。作为朝着这个方向迈出的一步，我们提供了一个在线资源 (http://www.humous.org)，用于编译小鼠胚胎胚胎发育和神经元分化的转录图，人类胚胎和人类大脑类器官。结论 使用选定的例子，我们强调了几个层次（即遗传、分子、细胞、回路和行为），在皮质畸形期间发生的组合相互作用和阻碍了对疾病过程的因果关系的理解。为个体患者辨别每个层面所涉及的过程是为他们及其家人提供预后指标和治疗观点的关键。综合方法包括使用最先进的人工智能算法的患者电生理、成像、临床和生物数据，可以将 DNA 突变与分子、细胞、解剖和电路特征联系起来。这将有助于疾病的生理病理分类，这是患者分层和个性化诊断和治疗工具设计的重要一步。皮质畸形复杂性的出现。显示了皮质形成过程中的组织水平，从基因到基因表达（RNA 和蛋白质）、细胞、回路和解剖结构以及表型。每个圆圈代表该级别的一个给定特征。级别内的交互通过复杂的关系与其他级别的状态相关联。突出显示了跨疾病级别的异常线性（白兰地红色）、收敛（青色）和发散（蓝色）特征关系的示例。大脑皮层是一个复杂的结构，控制着人类的语言和认知等功能。皮质功能依赖于复杂的分子和细胞相互作用在发育过程中出现的特殊神经元。当这些步骤中的一个或几个执行不正确时，就会发生神经发育障碍。尽管已经确定了许多致病基因和疾病表型，但将分子破坏与临床表达联系起来的事件序列大多仍不清楚。在这里，我们重点关注皮质发育的人类畸形，说明遗传、细胞和回路水平上的复杂相互作用如何共同导致疾病表型的多样性和变异性。使用具体示例和在线资源，我们建议对疾病过程进行多层次评估是识别脆弱点和开发新治疗策略的关键。将分子破坏与临床表现联系起来的事件序列大多仍不清楚。在这里，我们重点关注皮质发育的人类畸形，说明遗传、细胞和回路水平上的复杂相互作用如何共同导致疾病表型的多样性和变异性。使用具体示例和在线资源，我们建议对疾病过程进行多层次评估是识别脆弱点和开发新治疗策略的关键。将分子破坏与临床表现联系起来的事件序列大多仍不清楚。在这里，我们重点关注皮质发育的人类畸形，说明遗传、细胞和回路水平上的复杂相互作用如何共同导致疾病表型的多样性和变异性。使用具体示例和在线资源，我们建议对疾病过程进行多层次评估是识别脆弱点和开发新治疗策略的关键。