Manuscript:
Organoids of the human basal ganglia reveal biased development of medial over caudal ganglionic eminence fates in Autism risk-gene mutants

Abstract:
The medial, lateral, and caudal ganglionic eminences (MGE, LGE and CGE) are the source of a rich diversity of neuronal lineages, including several GABAergic neuronal populations of the cerebral cortex and striatum that are critical for forebrain function and which are affected in neurodevelopmental disorders. Here, we developed a human brain organoid model capable of reproducible co-development of all three ganglionic eminences and their derivatives. Notably, this model produces lineages of the CGE, which have not been previously reported in organoids. We extensively profiled multiple time points of organoid differentiation by single-cell RNA-sequencing, providing a first reconstruction of developmental trajectories of multiple cell lineages emerging from the three ganglionic eminences in organoids and allowing a description of the molecular programs underlying their specification. We leveraged the ability to map dynamics of development of these many separate lineages to discover that organoids carrying mutations in the ASD risk gene CHD8 display a previously unappreciated developmental defect whereby MGE derivatives preferentially develop at the expense of CGE derivatives. This caused asynchronous generation of large populations of ventrally derived forebrain neurons, resulting in loss of normal synchronous activity of the cortical local circuit. This model of the human ganglionic eminences provides insight into the mechanisms controlling the development of multiple major GABAergic lineages of the human ventral forebrain, and enables the study of developmental abnormalities affecting these neuronal populations