Abstract
Foxg1 is one of the forkhead box genes that are involved in morphogenesis, cell fate determination, and proliferation, and Foxg1 was previously reported to be required for morphogenesis of the mammalian inner ear. However, Foxg1 knock-out mice die at birth, and thus the role of Foxg1 in regulating hair cell (HC) regeneration after birth remains unclear. Here we used Sox2CreER/+ Foxg1loxp/loxp mice and Lgr5-EGFPCreER/+ Foxg1loxp/loxp mice to conditionally knock down Foxg1 specifically in Sox2+ SCs and Lgr5+ progenitors, respectively, in neonatal mice. We found that Foxg1 conditional knockdown (cKD) in Sox2+ SCs and Lgr5+ progenitors at postnatal day (P)1 both led to large numbers of extra HCs, especially extra inner HCs (IHCs) at P7, and these extra IHCs with normal hair bundles and synapses could survive at least to P30. The EdU assay failed to detect any EdU+ SCs, while the SC number was significantly decreased in Foxg1 cKD mice, and lineage tracing data showed that much more tdTomato+ HCs originated from Sox2+ SCs in Foxg1 cKD mice compared to the control mice. Moreover, the sphere-forming assay showed that Foxg1 cKD in Lgr5+ progenitors did not significantly change their sphere-forming ability. All these results suggest that Foxg1 cKD promotes HC regeneration and leads to large numbers of extra HCs probably by inducing direct trans-differentiation of SCs and progenitors to HCs. Real-time qPCR showed that cell cycle and Notch signaling pathways were significantly down-regulated in Foxg1 cKD mice cochlear SCs. Together, this study provides new evidence for the role of Foxg1 in regulating HC regeneration from SCs and progenitors in the neonatal mouse cochlea.
Highlights
The loss of hair cells (HCs) is the main cause of sensorineural hearing loss, which is one of the most common health problems around the world
We statistically analyzed the number of total inner HCs (IHCs), outer HC (OHC), and supporting cells (SCs) per 100 μm cochlea length, and found significantly more IHCs in the cochleae of Foxg1 conditional knockdown (cKD) mice compared to S ox2CreER/+ control mice, and the number of extra IHCs decreased from the apical turns to the basal turns (Fig. 1f and j, Table S2)
As previously reported [29, 30], we quantified the numbers of various cell types of SCs and found that the numbers of inner pillar cells (IPCs) and outer pillar cells (OPCs) were significantly decreased in the apical and middle turns of Foxg1 cKD mice cochleae, respectively (Fig. 1i, j and k), which suggest that the extra HCs might be generated by direct trans-differentiation of SCs
Summary
The loss of hair cells (HCs) is the main cause of sensorineural hearing loss, which is one of the most common health problems around the world. The up-regulation of canonical Wnt signaling induces the proliferation of sensory precursors in the postnatal mouse cochlea [3, 4, 11,12,13,14,15,16,17], while Notch inhibition induces mitotic generation of HCs in the mammalian cochlea via activation of the Wnt pathway [12, 14, 18,19,20,21,22,23,24,25] Their effect on differentiation and the generation of HCs is related to important genes such as Atoh and Neurog1 [26,27,28,29,30,31,32,33,34]. Due to the postnatal lethality of Foxg1-null mice, the roles of Foxg in HC regeneration in the postnatal mouse cochlea have remained unknown
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