During embryonic development, excitatory projection neurons migrate in the cerebral cortex giving rise to organised layers. Periventricular heterotopia (PH) is a group of aetiologically heterogeneous disorders in which a subpopulation of newborn projection neurons fails to initiate their radial migration to the cortex, ultimately resulting in bands or nodules of grey matter lining the lateral ventricles. Although a number of genes have been implicated in its cause, currently they only satisfactorily explain the pathogenesis of the condition for 50% of patients. Novel gene discovery is complicated by the extreme genetic heterogeneity recently described to underlie its cause. Here, we study the neurodevelopmental role of endothelin-converting enzyme-2 (ECE2) for which two biallelic variants have been identified in two separate patients with PH. Our results show that manipulation of ECE2 levels in human cerebral organoids and in the developing mouse cortex leads to ectopic localisation of neural progenitors and neurons. We uncover the role of ECE2 in neurogenesis, and mechanistically, we identify its involvement in the generation and secretion of extracellular matrix proteins in addition to cytoskeleton and adhesion.

中文翻译：

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ECE2调节人类皮质发育过程中的神经发生和神经元迁移。

在胚胎发育过程中，兴奋性投射神经元在大脑皮层中迁移，从而形成有组织的层。脑室周围异位症（PH）是一组病因异质性疾病，其中新生投射神经元的亚群未能启动其径向向皮层的迁移，最终导致侧脑室衬有灰质带或结节。尽管已经有许多基因与其病因有关，但目前它们仅能令人满意地解释50％患者的病因。新基因的发现由于最近被描述为其原因的极端遗传异质性而变得复杂。在这里，我们研究了内皮素转化酶2（ECE2）在两个独立的PH患者中鉴定出两个双等位基因变异体的神经发育作用。我们的结果表明，在人脑类器官和发育中的小鼠皮质中ECE2水平的操纵会导致神经祖细胞和神经元的异位定位。我们揭示了ECE2在神经发生中的作用，并且在机制上，我们确定了ECE2参与了细胞骨架和粘附以及细胞外基质蛋白的产生和分泌。