Renshaw Cells and Ia Inhibitory Interneurons Are Generated at Different Times from P1 Progenitors and Differentiate Shortly After Exiting the Cell Cycle

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Spinal interneurons modulating motor output are highly diverse but surprisingly arise from just a few embryonic subgroups. The principles governing their development, diversification, and integration into spinal circuits are unknown. This study focuses on the differentiation of adult Renshaw cells (RCs) and Ia inhibitory interneurons (IaINs), two subclasses that respectively mediate recurrent and reciprocal inhibition of motoneurons from embryonic V1 interneurons (V1-INs). V1-INs originate from p1 progenitors and, after they become postmitotic, specifically express the transcription factor engrailed-1, a property that permits genetic labeling of V1 lineages from embryo to adult. RCs and IaINs are V1 derived, but differ in morphology, location, calcium-binding protein expression, synaptic connectivity, and function. These differences are already present in neonates, and in this study we show that their differentiation starts in the early embryo. Using 5′-bromodeoxyuridine birth dating we established that mouse V1-INs can be divided into early (E9.5-E10.5) and late (E11.5-E12.5) groups generated from the p1 domain (where E is embryonic day). The early group upregulates calbindin expression soon after becoming postmitotic and includes RCs, which express the transcription factor MafB during early differentiation and maintain calbindin expression throughout life. The late group includes IaINs, are calbindin-negative, and express FoxP2 at the start of differentiation. Moreover, developing RCs follow a characteristic circumferential migratory route that places them in unique relationship with motor axons with whom they later synaptically interact. We conclude that the fate of these V1-IN subclasses is determined before synaptogenesis and circuit formation by a process that includes differences in neurogenesis time, transcription factor expression, and migratory pathways.