Spatiotemporal clonal architecture of the newborn mouse forebrain

How hundreds of cell types of the mammalian forebrain emerge from a limited set of progenitor cells during development remains largely unknown^1-3, and studies so far have overwhelmingly focused on the cerebral cortex. Here, to fill this gap, we applied lentiviral barcoding across the major subdivisions of the mouse forebrain: cortex, hippocampus, striatum, thalamus and olfactory bulb. We registered cellular profiles to their anatomical distribution using spatial transcriptomics, creating an atlas of clonal cell lineage relationships across a newborn mouse forebrain. We uncover previously unrecognized differences in generation of ventral and dorsal medium spiny neurons, as well as unexplored lineage relationships between late-born medium spiny neurons, striatal astrocytes and distinct subpopulations of the olfactory bulb neurons. We show that clones of GABAergic (γ-aminobutyric acid-producing) neurons with broad regional dispersion are enriched for genes implicated in neurodevelopmental disorders. Our results highlight a developmental principle whereby glutamatergic neurons and astrocytes are clonally related and retained within their region of origin, whereas GABAergic neurons are clonally related to oligodendrocyte precursor cells but disperse extensively across brain regions. Together, our findings will serve as a foundational reference for studies of mammalian forebrain development and its disorders.