期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2206571119
关键词
Sufu; Shh signaling; Gli; hair cell; cochlea
资金
- Research Grant Council in Hong Kong [RGC GRF 17159316]
- Canadian Institutes of Health Research
- Canada Research Chairs program
This study reveals that Sufu and Spop play crucial roles in controlling the timing and progression of sensory cell differentiation in the development of mammalian auditory epithelium. They maintain the progenitor state of sensory progenitor cells through regulation of the Shh-Gli2 signaling pathway, thus preventing hair cell differentiation.
Development of mammalian auditory epithelium, the organ of Corti, requires precise control of both cell cycle withdrawal and differentiation. Sensory progenitors (prosensory cells) in the cochlear apex exit the cell cycle first but differentiate last. Sonic hedgehog (Shh) signaling is required for the spatiotemporal regulation of prosensory cell differentia-tion, but the underlying mechanisms remain unclear. Here, we show that suppressor of fused (Sufu), a negative regulator of Shh signaling, is essential for controlling the timing and progression of hair cell (HC) differentiation. Removal of Sufu leads to abnormal Atoh1 expression and a severe delay of HC differentiation due to elevated Gli2 mRNA expression. Later in development, HC differentiation defects are restored in the Sufu mutant by the action of speckle-type PDZ protein (Spop), which promotes Gli2 protein degradation. Deletion of both Sufu and Spop results in robust Gli2 activation, exacerbat-ing HC differentiation defects. We further demonstrate that Gli2 inhibits HC differentia-tion through maintaining the progenitor state of Sox2+ prosensory cells. Along the basal-apical axis of the developing cochlea, the Sox2 expression level is higher in the pro-genitor cells than in differentiating cells and is down-regulated from base to apex as differ-entiation proceeds. The dynamic spatiotemporal change of Sox2 expression levels is controlled by Shh signaling through Gli2. Together, our results reveal key functions of Gli2 in sustaining the progenitor state, thereby preventing HC differentiation and in turn governing the basal-apical progression of HC differentiation in the cochlea.
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