Organizers in a dish: Modeling human CNS morphogenesis

The human brain stands out for the scale of cellular and morphological complexity across anterior-posterior domains. Modeling the entire neuraxis is therefore essential to comprehend human neural development and disease. Brain organoids commonly recapitulate anterior regions due to the propensity of neural progenitors to acquire telencephalic identities and self-organize into cortical layers. In the embryo, posterior brain patterning is orchestrated by organizers, signaling centers positioned at anterior-posterior locations that are rarely induced in vitro . Several strategies have been developed to reproduce organizer signals, employing small molecules and recombinant morphogens, thereby expanding the in vitro repertoire of human neural identities. Despite this, posterior models do not yet reproduce the morphological complexity of their in vivo counterparts. In this review, we discuss how this discrepancy may stem from the inability to recapitulate the spatiotemporal dynamics of organizer activity and how recent technologies can balance guided differentiation and self-organization, enhancing the fidelity of human brain organoid models. In this review, Miller et al. navigate through the key organizers that shape CNS development and draw in vivo-in vitro parallels with corresponding human organoid models, highlighting how balancing guided differentiation with self-organization may help bridge the remaining gap between in vitro and in vivo systems.