Abstract
The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such cellular mosaic ensures the balanced activity of the two pathways, its developmental origin and pattern remains largely unknown. Here, we show that both SPN populations are specified embryonically and intermix progressively through multidirectional iSPN migration. Using conditional mutant mice, we found that inactivation of the dSPN-specific transcription factor Ebf1 impairs selective dSPN properties, including axon pathfinding, while molecular and functional features of iSPN were preserved. Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, highlighting that intermixing is a parallel process to compartment formation. Our study reveals while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.
Highlights
The striatum controls behaviors via the activity of direct and indirect pathway projection neurons that are intermingled in all compartments
Using these two mouse lines, we found that indirect SPN (iSPN) and direct SPN (dSPN) lineages are non-overlapping throughout embryogenesis, consistently with previous studies focusing on striatal projection neurons (SPN) subtypes specification[16,24,26,27,28,29]
Our findings indicate that dSPN and iSPN exhibit distinct molecular identities from the earliest steps of striatogenesis and provides us with tools to follow their integration in the striatal architecture
Summary
The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. Building on this relatively simple cellular organization, the dorsal striatum is split into at least two major compartments, cellular islands known as striosomes and a surrounding matrix, which form immunohistologically and functionally distinct modules differing by their input and output patterns of connectivity[7,8,9,10,11] In such precise three-dimensional organization, the intermingling of dSPN and iSPN ensures the balanced activation of direct and indirect pathways. We found that Ebf[1] deletion in dSPN (i) perturbed specific aspects of direct neurons differentiation, leading to defective axogenesis and integration in cortico-striatal circuits, without affecting iSPN cardinal properties (ii) impaired intermixing of dSPN and iSPN in the matrix. Our study reveals that the active intermingling of early-specified dSPN and iSPN is required to assemble the striatal mosaic
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