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. 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.
Proper tissue development requires strict coordination of proliferation, growth, and differentiation. Strict coordination is particularly important for the auditory sensory epithelium, where deviations from the normal spatial and temporal pattern of auditory progenitor cell (prosensory cell) proliferation and differentiation result in abnormal cellular organization and, thus, auditory dysfunction. The molecular mechanisms involved in the timing and coordination of auditory prosensory proliferation and differentiation are poorly understood. Here we identify the RNAbinding protein LIN28B as a critical regulator of developmental timing in the murine cochlea. We show that Lin28b and its opposing let-7 miRNAs are differentially expressed in the auditory sensory lineage, with Lin28b being highly expressed in undifferentiated prosensory cells and let-7 miRNAs being highly expressed in their progeny-hair cells (HCs) and supporting cells (SCs). Using recently developed transgenic mouse models for LIN28B and let-7g, we demonstrate that prolonged LIN28B expression delays prosensory cell cycle withdrawal and differentiation, resulting in HC and SC patterning and maturation defects. Surprisingly, let-7g overexpression, although capable of inducing premature prosensory cell cycle exit, failed to induce premature HC differentiation, suggesting that LIN28B's functional role in the timing of differentiation uses let-7 independent mechanisms. Finally, we demonstrate that overexpression of LIN28B or let-7g can significantly alter the postnatal production of HCs in response to Notch inhibition; LIN28B has a positive effect on HC production, whereas let-7 antagonizes this process. Together, these results implicate a key role for the LIN28B/let-7 axis in regulating postnatal SC plasticity.Lin28b | Let-7 | hair cell | cochlea | regeneration
Mechano-sensory hair cells (HCs), housed in the inner ear cochlea, are critical for the perception of sound. In the mammalian cochlea, differentiation of HCs occurs in a striking basal-to-apical and medial-to-lateral gradient, which is thought to ensure correct patterning and proper function of the auditory sensory epithelium. Recent studies have revealed that Hedgehog signaling opposes HC differentiation and is critical for the establishment of the graded pattern of auditory HC differentiation. However, how Hedgehog signaling interferes with HC differentiation is unknown. Here, we provide evidence that in the murine cochlea, Hey1 and Hey2 control the spatiotemporal pattern of HC differentiation downstream of Hedgehog signaling. It has been recently shown that HEY1 and HEY2, two highly redundant HES-related transcriptional repressors, are highly expressed in supporting cell (SC) and HC progenitors (prosensory cells), but their prosensory function remained untested. Using a conditional double knock-out strategy, we demonstrate that prosensory cells form and proliferate properly in the absence of Hey1 and Hey2 but differentiate prematurely because of precocious upregulation of the pro-HC factor Atoh1. Moreover, we demonstrate that prosensory-specific expression of Hey1 and Hey2 and its subsequent graded downregulation is controlled by Hedgehog signaling in a largely FGFR-dependent manner. In summary, our study reveals a critical role for Hey1 and Hey2 in prosensory cell maintenance and identifies Hedgehog signaling as a novel upstream regulator of their prosensory function in the mammalian cochlea. The regulatory mechanism described here might be a broadly applied mechanism for controlling progenitor behavior in the central and peripheral nervous system.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.