The circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of these organizations and their developmental relationships are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIP S s) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIP M s) with expanded capacity. Notably, direct and indirect pathway SPNs arise within both aIP S and bIP M pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry. In this article, Kelly et al. describe a lineage program embedded in lateral ganglionic eminence progenitors responsible for striosome-matrix compartmentalization in striatum.
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