Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

Autor: Ying Dong, Guodong Hong, Han Zhou, Shasha Zhang, Xia Gao, Jieyu Qi, Zhong Zhang, Lingna Guo, Chunjie Zhao, Liyan Zhang, Xiaoli Zhang, Weijie Zhu, Mingliang Tang, Renjie Chai, Xiaoqian Yan, Yuan Zhang, Buwei Shao
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Cell Survival
Proliferation
Notch signaling pathway
Trans-differentiation
Progenitors
Cell Count
Mice
Transgenic
Nerve Tissue Proteins
Cell fate determination
Biology
Foxg1
Hair cells
Mechanotransduction
Cellular
Receptors
G-Protein-Coupled
03 medical and health sciences
Cellular and Molecular Neuroscience
SOX2
Supporting cells
Hair Cells
Auditory
medicine
Animals
Cell Lineage
Progenitor cell
Molecular Biology
Cochlea
Cell Proliferation
Pharmacology
0303 health sciences
Gene knockdown
Stem Cells
030302 biochemistry & molecular biology
LGR5
Labyrinth Supporting Cells
Forkhead Transcription Factors
Cell Biology
Cell biology
medicine.anatomical_structure
Animals
Newborn
Gene Expression Regulation
Gene Knockdown Techniques
Cell Transdifferentiation
Synapses
Molecular Medicine
Original Article
Hair cell
sense organs
Signal Transduction
Zdroj: Cellular and Molecular Life Sciences
ISSN: 1420-9071
1420-682X
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s00018-019-03291-2) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
Externí odkaz: