Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea

Atkinson, Patrick; Dong, Yaodong; Gu, Shaohua; Liu, Wenwen; Najarro, Elvis Huarcaya; Udagawa, Takashi; Cheng, Alan G.

doi:10.1172/jci97248

Cited by 64 publications

(60 citation statements)

References 88 publications

(99 reference statements)

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“…1e, g and h). Although extra IHCs could also be seen in the cochleae of Sox2 CreER/+ control mice due to Sox2 haploinsufficiency as reported recently [76,77], statistical analysis showed that there were significantly more extra IHCs in the Foxg1 cKD mice compared to the controls (Fig. 1f).…”

Section: Foxg1 Ckd In Neonatal Mouse Cochlear Scs Led To Significantlsupporting

confidence: 67%

“…One recent report showed that Sox2 haploinsufficiency (Sox2-CreER, Sox2-EGFP, in which one allele of the Sox2 gene is replaced by CreER or EGFP such that Sox2 is expressed at only half of the normal expression level) also increases the IHC number in vivo [76,77]. Thus in our study, we also used Sox2 CreER/+ mice as the control to avoid overestimating the effect of cKD of Foxg1.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Dong

et al. 2019

Cell. Mol. Life Sci.

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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 Sox2 CreER/+ Foxg1 loxp/loxp mice and Lgr5-EGFP CreER/+ Foxg1 loxp/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 sphereforming 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.

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Section: Foxg1 Ckd In Neonatal Mouse Cochlear Scs Led To Significantlsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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

Zhang

Dong

et al. 2019

Cell. Mol. Life Sci.

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“…Likewise, the ability of murine cochlear supporting cells to produce hair cells sharply declines during the first postnatal week (27,48) and little to no hair cell production/ regeneration is observed within the cochlea of adult mice (14,17,65). The reason for the decline in supporting cell plasticity is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we found that LIN28B overexpression led to a transient downregulation in Sox2 mRNA expression at the peak of organoid expansion. Recent studies found that SOX2 positively regulates p27/Kip1 transcription and reduction in Sox2 expression primes cochlear supporting cells for proliferation and hair cell regeneration (47,65). Future studies are warranted to address LIN28B's role in Sox2 expression during hair cell regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it needs to be emphasized that our study was conducted in vitro and was limited to immature, early postnatal stages. While recent studies showed promise in regenerating vestibular hair cells in adult mice (9,82), the regeneration of cochlear hair cells in adult mice has proven thus far an impossible task (65) and reviewed in (83).…”

Section: Discussionmentioning

confidence: 99%

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LIN28B controls the regenerative capacity of neonatal murine auditory supporting cells through activation of mTOR signaling

Doetzlhofer

2020

Preprint

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Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells.However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mTOR activity. Employing murine cochlear organoid and explant cultures to model mitotic and non-mitotic mechanisms of hair cell generation, we show that loss of Lin28b function, due to its conditional deletion, or due to overexpression of the antagonistic miRNA let-7g, suppressed Akt-mTORC1 activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and non-mitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner. SIGNIFICANCE STATEMENTCochlear hair cell loss is a leading cause of deafness in humans and other mammals. In the immature cochlea lost hair cells are regenerated by neighboring glia-like supporting cells. However, for reasons unknown, such regenerative capacity is rapidly lost as supporting cells undergo maturation. Here we identify a direct link between LIN28B-mTOR activity and supporting cell plasticity. Mimicking later developmental stages, we found that loss of the RNA binding protein LIN28B attenuated mTOR signaling and rendered young, immature supporting cells incapable of producing hair cells. Conversely, we found Recent studies uncovered that as early as postnatal day 5/6 (P5/P6) murine cochlear supporting cells fail to regenerate hair cells in response to injury (14), inhibition of Notch signaling (26), or over-activation of Wnt/β-catenin signaling (27). What causes the rapid decline in supporting cell plasticity during the first postnatal week is currently unknown. We previously demonstrated that a regulatory circuit consisting of LIN28B and let-7 miRNAs modulates the production of new hair cells in stage P2 murine cochlear explants, with LIN28B promoting new hair cell production and let-7 miRNAs suppressing it (28). The closely related RNA binding proteins LIN28A and LIN28B (LIN28A/B) and members of the let-7 family of miRNAs belong to an evolutionary highly conserved network of genes, initially identified in C-elegans for their role in d...

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FUBP1 promotes colorectal cancer stemness and metastasis via DVL1‐mediated activation of Wnt/β‐catenin signaling

et al. 2021

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Distant metastasis is, unfortunately, the leading cause of death in colorectal cancer (CRC). Approximately 50% of CRC patients develop liver metastases, while 10-30% of patients develop pulmonary metastases. The occurrence of metastasis is considered to be almost exclusively driven by cancer stem cells (CSCs) formation. However, the key molecules that confer the transformation to stem cells in CRC, and subsequent metastasis, remain unclear. Far upstream element-binding protein 1 (FUBP1), a transcriptional regulator of c-Myc, was screened in CSCs of CRC by mass spectrometry and was examined by immunohistochemistry in a cohort of CRC tissues. FUBP1 was upregulated in 85% of KRAS-mutant and 25% of wild-type CRC patients. Further, whether in KRAS-mutant or wild-type patients, elevated FUBP1 was positively correlated with CRC lymph node metastasis and clinical stage, and negatively associated with overall survival. Overexpression of FUBP1 significantly enhanced CRC cell migration, invasion, tumor sphere formation, and CD133 and ALDH1 expression in vitro, and tumorigenicity in vivo. Mechanistically, FUBP1 promoted the initiation of CSCs by activating Wnt/b-catenin signaling via directly binding to the promoter of DVL1, a potent activator of b-catenin. Knockdown of DVL1 significantly inhibited the transformation to stem cells in, as well as the tumorigenicity of, CRC. Activation of Wnt/b-catenin signaling by DVL1 increased pluripotent transcription factors, including c-Myc, NANOG, and SOX2. Moreover, FUBP1 was upregulated at the post-transcriptional level. Elevated FUBP1 levels in KRAS wild-type CRC patients is due to the decrease in Smurf2, which promotes ubiquitinmediated degradation of FUBP1. In contrast, FUBP1 was upregulated in KRAS-mutant patients through both inhibition of caspase 3-dependent cleavage and decreased Smurf2. Our results demonstrate, for the first time, that FUBP1 is an oncogene, initiating the development of CSCs, as well as Abbreviations ChIP, chromatin immunoprecipitation; CRC, colorectal cancer; CSCs, cancer stem cells; FUBP1, far upstream element-binding protein 1; IHC, immunohistochemistry; Real-time PCR, quantitative real-time polymerase chain reaction.

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Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea

Cited by 64 publications

References 88 publications

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

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

LIN28B controls the regenerative capacity of neonatal murine auditory supporting cells through activation of mTOR signaling

FUBP1 promotes colorectal cancer stemness and metastasis via DVL1‐mediated activation of Wnt/β‐catenin signaling

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