Anatomy-Informed Modeling of Human Ciliopathy with Brain Organoids
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Brain organoids offer unprecedented opportunities to model human neurodevelopment in a threedimensional, anatomically relevant context. In this review, we focus on ciliopathies, such as Joubert and MeckelGruber syndromes, which represent a group of neurodevelopmental disorders characterized by overt anatomical malformations including disrupted ventricular organization, midline defects, and cerebellar hypoplasia. These conditions underscore the central role of primary cilia in orchestrating spatial patterning and morphogenesis of the human brain. Building on this anatomical framework, we discuss how brain organoids, by self-organizing into regionally specified, polarity-maintained structures, serve as powerful platforms to investigate the developmental consequences of ciliary dysfunction in a human-specific manner. Notably, this review synthesizes recent organoidbased models of key ciliopathy-related genes, such as RPGRIP1L, INPP5E, and ARL13B, and demonstrates how each mutation leads to distinct disruptions in rostro-caudal or dorsoventral brain patterning. These structural phenotypes, often undetectable in animal models, underscore the added value of organoids in modeling human ciliopathies. By integrating insights from developmental neurobiology with an anatomical perspective, this review provides a structurally grounded lens to interpret the pathogenesis of ciliopathy and underscores the emerging utility of brain organoids as both mechanistic and morphological disease models.
Abstract
Brain organoids offer unprecedented opportunities to model human neurodevelopment in a threedimensional, anatomically relevant context. In this review, we focus on ciliopathies, such as Joubert and MeckelGruber syndromes, which represent a group of neurodevelopmental disorders characterized by overt anatomical malformations including disrupted ventricular organization, midline defects, and cerebellar hypoplasia. These conditions underscore the central role of primary cilia in orchestrating spatial patterning and morphogenesis of the human brain. Building on this anatomical framework, we discuss how brain organoids, by self-organizing into regionally specified, polarity-maintained structures, serve as powerful platforms to investigate the developmental consequences of ciliary dysfunction in a human-specific manner. Notably, this review synthesizes recent organoidbased models of key ciliopathy-related genes, such as RPGRIP1L, INPP5E, and ARL13B, and demonstrates how each mutation leads to distinct disruptions in rostro-caudal or dorsoventral brain patterning. These structural phenotypes, often undetectable in animal models, underscore the added value of organoids in modeling human ciliopathies. By integrating insights from developmental neurobiology with an anatomical perspective, this review provides a structurally grounded lens to interpret the pathogenesis of ciliopathy and underscores the emerging utility of brain organoids as both mechanistic and morphological disease models.