Mapping the molecular and cellular complexity of cortical malformations

Abstract

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.