Genetic risk for autism spectrum disorders (ASD) is associated with hundreds of genes spanning a wide range of biological functions 1-6 . The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals 6,7 . Here, we leveraged organoid models of the human cerebral cortex to identify cell type-specific developmental abnormalities resulting from haploinsufficiency in three ASD risk genes, SUV420H1 (KMT5B), ARID1B, and CHD8, in multiple cell lines from different donors, using single-cell RNA-seq (scRNA-seq) of over 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations demonstrates asynchronous development of two main cortical neuronal lineages, GABAergic neurons and deep-layer excitatory projection neurons, but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This work uncovers cell typespecific neurodevelopmental abnormalities shared across ASD risk genes that are finely modulated Paulsen et al.

The cerebral cortex is a highly organized structure whose development depends on diverse progenitor cell types, namely apical radial glia, intermediate progenitors, and basal radial glia cells, which are responsible for the production of the correct neuronal output. In recent years, these progenitor cell types have been deeply studied, particularly basal radial glia and their role in cortical expansion and gyrification. We review here a broad series of factors that regulate progenitor behavior and daughter cell fate. We first describe the different neuronal progenitor types, emphasizing the differences between lissencephalic and gyrencephalic species. We then review key factors shown to influence progenitor proliferation versus differentiation, discussing their roles in progenitor dynamics, neuronal production, and potentially brain size and complexity. Although spindle orientation has been considered a critical factor for mode of division and daughter cell output, we discuss other features that are emerging as crucial for these processes such as organelle and cell cycle dynamics. Additionally, we highlight the importance of adhesion molecules and the polarity complex for correct cortical development. Finally, we briefly discuss studies assessing progenitor multipotency and its possible contribution to the production of specific neuronal populations. This review hence summarizes recent aspects of cortical progenitor cell biology, and pinpoints emerging features critical for their behavior.