The Experts below are selected from a list of 1935 Experts worldwide ranked by ideXlab platform
Chunjie Zhao - One of the best experts on this subject based on the ideXlab platform.
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knockdown of FOXG1 in sox9 supporting cells increases the trans differentiation of supporting cells into hair cells in the neonatal mouse utricle
Aging, 2020Co-Authors: Yuan Zhang, Chunjie Zhao, Shasha Zhang, Zhonghong Zhang, Ying Dong, Ruiying Qiang, Yin Chen, Xia Gao, Fangyi Chen, Renjie ChaiAbstract:FOXG1 plays important roles in regeneration of hair cell (HC) in the cochlea of neonatal mouse. Here, we used Sox9-CreER to knock down FOXG1 in supporting cells (SCs) in the utricle in order to investigate the role of FOXG1 in HC regeneration in the utricle. We found Sox9 an ideal marker of utricle SCs and bred Sox9CreER/+FOXG1loxp/loxp mice to conditionally knock down FOXG1 in utricular SCs. Conditional knockdown (cKD) of FOXG1 in SCs at postnatal day one (P01) led to increased number of HCs at P08. These regenerated HCs had normal characteristics, and could survive to at least P30. Lineage tracing showed that a significant portion of newly regenerated HCs originated from SCs in FOXG1 cKD mice compared to the mice subjected to the same treatment, which suggested SCs trans-differentiate into HCs in the FOXG1 cKD mouse utricle. After neomycin treatment in vitro, more HCs were observed in FOXG1 cKD mice utricle compared to the control group. Together, these results suggest that FOXG1 cKD in utricular SCs may promote HC regeneration by inducing trans-differentiation of SCs. This research therefore provides theoretical basis for the effects of FOXG1 in trans-differentiation of SCs and regeneration of HCs in the mouse utricle.
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loss of FOXG1 impairs the development of cortical sst interneurons leading to abnormal emotional and social behaviors
Cerebral Cortex, 2019Co-Authors: Dongsheng Chen, Chunlian Wang, Xinyu She, Yonggui Yuan, Huanxin Chen, Weining Zhang, Chunjie ZhaoAbstract:FOXG1 syndrome is a severe encephalopathy that exhibit intellectual disability, emotional disorder, and limited social communication. To elucidate the contribution of somatostatin-expressing interneurons (SST-INs) to the cellular basis underlying FOXG1 syndrome, here, by crossing SST-cre with a FOXG1fl/fl line, we selectively ablated FOXG1. Loss of FOXG1 resulted in an obvious reduction in the number of SST-INs, accompanied by an altered ratio of subtypes. FOXG1-deficient SST-INs exhibited decreased membrane excitability and a changed ratio of electrophysiological firing patterns, which subsequently led to an excitatory/inhibitory imbalance. Moreover, cognitive defects, limited social interactions, and depression-like behaviors were detected in FOXG1 cKO mice. Treatment with low-dose of clonazepam effectively alleviated the defects. These results identify a link of SST-IN development to the aberrant emotion, cognition, and social capacities in patients. Our findings identify a novel role of FOXG1 in SST-IN development and put new insights into the cellular basis of FOXG1 syndrome.
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FOXG1 Regulates the Postnatal Development of Cortical Interneurons.
Cerebral cortex (New York N.Y. : 1991), 2018Co-Authors: Wei Shen, Dongsheng Chen, Wei Xie, Samuel J. Pleasure, Chunjie ZhaoAbstract:Abnormalities in cortical interneurons are closely associated with neurological diseases. Most patients with FOXG1 syndrome experience seizures, suggesting a possible role of FOXG1 in the cortical interneuron development. Here, by conditional deletion of FOXG1, which was achieved by crossing FOXG1fl/fl with the Gad2-CreER line, we found the postnatal distributions of somatostatin-, calretinin-, and neuropeptide Y-positive interneurons in the cortex were impaired. Further investigations revealed an enhanced dendritic complexity and decreased migration capacity of FOXG1-deficient interneurons, accompanied by remarkable downregulation of Dlx1 and CXCR4. Overexpression of Dlx1 or knock down its downstream Pak3 rescued the differentiation detects, demonstrated that FOXG1 functioned upstream of Dlx1-Pak3 signal pathway to regulate the postnatal development of cortical interneurons. Due to the imbalanced neural circuit, FOXG1 mutants showed increased seizure susceptibility. These findings will improve our understanding of the postnatal development of interneurons and help to elucidate the mechanisms underlying seizure in patients carrying FOXG1 mutations.
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FOXG1 deletion impairs the development of the epithalamus
Molecular Brain, 2018Co-Authors: Kaixing Zhou, Xiaojing Wu, Chunjie ZhaoAbstract:The epithalamus, which is dorsal to the thalamus, consists of the habenula, pineal gland and third ventricle choroid plexus and plays important roles in the stress response and sleep–wake cycle in vertebrates. During development, the epithalamus arises from the most dorsal part of prosomere 2. However, the mechanism underlying epithalamic development remains largely unknown. FOXG1 is critical for the development of the telencephalon, but its role in diencephalic development has been under-investigated. Patients suffering from FOXG1-related disorders exhibit severe anxiety, sleep disturbance and choroid plexus cysts, indicating that FOXG1 likely plays a role in epithalamic development. In this study, we identified the specific expression of FOXG1 in the developing epithalamus. Using a “self-deletion” approach, we found that the habenula significantly expanded and included an increased number of habenular subtype neurons. The innervations, particularly the habenular commissure, were severely impaired. Meanwhile, the FOXG1 mutants exhibited a reduced pineal gland and more branched choroid plexus. After ablation of FOXG1 no obvious changes in Shh and Fgf signalling were observed, suggesting that FOXG1 regulates the development of the epithalamus without the involvement of Shh and Fgfs. Our findings provide new insights into the regulation of the development of the epithalamus.
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FOXG1 has an essential role in postnatal development of the dentate gyrus
The Journal of Neuroscience, 2012Co-Authors: Chuanxi Tian, Yifan Gong, Ying Yang, Wei Shen, Kun Wang, Junhua Liu, Jing Zhao, Chunjie ZhaoAbstract:FOXG1, formerly BF-1, is expressed continuously in the postnatal and adult hippocampal dentate gyrus (DG). This transcription factor (TF) is thought to be involved in Rett syndrome, which is characterized by reduced hippocampus size, indicating its important role in hippocampal development. Due to the perinatal death of FOXG1−/− mice, the function of FOXG1 in postnatal DG neurogenesis remains to be explored. Here, we describe the generation of a FOXG1fl/fl mouse line. FOXG1 was conditionally ablated from the DG during prenatal and postnatal development by crossing this line with a Frizzled9-CreERTM line and inducing recombination with tamoxifen. In this study, we first show that disruption of FOXG1 results in the loss of the subgranular zone and a severely disrupted secondary radial glial scaffold, leading to the impaired migration of granule cells. Moreover, detailed analysis reveals that FOXG1 may be necessary for the maintenance of the DG progenitor pool and that the lack of FOXG1 promotes both gliogenesis and neurogenesis. We additionally show that FOXG1 may be required for the survival and maturation of postmitotic neurons and that FOXG1 may be involved in Reelin signaling in regulating postnatal DG development. Last, prenatal deletion of FOXG1 suggests that it is rarely involved in the migration of primordial granule cells. In summary, we report that FOXG1 is critical for DG formation, especially during early postnatal stage.
David Price - One of the best experts on this subject based on the ideXlab platform.
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the transcription factor FOXG1 promotes optic fissure closure in the mouse by suppressing wnt8b in the nasal optic stalk
The Journal of Neuroscience, 2017Co-Authors: Rowena Smith, Thomas Pratt, Yuting Huang, Tian Tian, Dominika Vojtasova, Oscar Mesallesnaranjo, Steven M Pollard, David Price, Vassiliki FotakiAbstract:During vertebrate eye morphogenesis, a transient fissure forms at its inferior part, known as the optic fissure. This will gradually close, giving rise to a healthy, spherical optic cup. Failure of the optic fissure to close gives rise to an ocular disorder known as coloboma. During this developmental process, FOXG1 is expressed in the optic neuroepithelium, with highest levels of expression in the nasal optic stalk. FOXG1-/- mutant mice have microphthalmic eyes with a large ventral coloboma. We found Wnt8b expression upregulated in the FOXG1-/- optic stalk and hypothesized that, similar to what is observed in telencephalic development, FOXG1 directs development of the optic neuroepithelium through transcriptional suppression of Wnt8b To test this, we generated FOXG1-/-;Wnt8b-/- double mutants of either sex and found that the morphology of the optic cup and stalk and the closure of the optic fissure were substantially rescued in these embryos. This rescue correlates with restored Pax2 expression in the anterior tip of the optic fissure. In addition, although we do not find evidence implicating altered proliferation in the rescue, we observe a significant increase in apoptotic cell density in FOXG1-/-;Wnt8b-/- double mutants compared with the FOXG1-/- single mutant. Upregulation of Wnt/β-catenin target molecules in the optic cup and stalk may underlie the molecular and morphological defects in the FOXG1-/- mutant. Our results show that proper optic fissure closure relies on Wnt8b suppression by FOXG1 in the nasal optic stalk to maintain balanced apoptosis and Pax2 expression in the nasal and temporal edges of the fissure.SIGNIFICANCE STATEMENT Coloboma is an ocular disorder that may result in a loss of visual acuity and accounts for ∼10% of childhood blindness. It results from errors in the sealing of the optic fissure (OF), a transient structure at the bottom of the eye. Here, we investigate the colobomatous phenotype of the FOXG1-/- mutant mouse. We identify upregulated expression of Wnt8b in the optic stalk of FOXG1-/- mutants before OF closure initiates. FOXG1-/-;Wnt8b-/- double mutants show a substantial rescue of the FOXG1-/- coloboma phenotype, which correlates with a rescue in molecular and cellular defects of FOXG1-/- mutants. Our results unravel a new role of FOXG1 in promoting OF closure providing additional knowledge about the molecules and cellular mechanisms underlying coloboma formation.
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the transcription factor FOXG1 regulates telencephalic progenitor proliferation cell autonomously in part by controlling pax6 expression levels
Neural Development, 2011Co-Authors: Martine Manuel, Ben Martynoga, John O Mason, Mike D Molinek, Jane Quinn, Corinne Kroemmer, David PriceAbstract:The transcription factor FOXG1 is an important regulator of telencephalic cell cycles. Its inactivation causes premature lengthening of telencephalic progenitor cell cycles and increased neurogenic divisions, leading to severe hypoplasia of the telencephalon. These proliferation defects could be a secondary consequence of the loss of FOXG1 caused by the abnormal expression of several morphogens (Fibroblast growth factor 8, bone morphogenetic proteins) in the telencephalon of FOXG1 null mutants. Here we investigated whether FOXG1 has a cell autonomous role in the regulation of telencephalic progenitor proliferation. We analysed FOXG1 +/+ ↔FOXG1 -/- chimeras, in which mutant telencephalic cells have the potential to interact with, and to have any cell non-autonomous defects rescued by, normal wild-type cells. Our analysis showed that the FOXG1 -/- cells are under-represented in the chimeric telencephalon and the proportion of them in S-phase is significantly smaller than that of their wild-type neighbours, indicating that their under-representation is caused by a cell autonomous reduction in their proliferation. We then analysed the expression of the cell-cycle regulator Pax6 and found that it is cell-autonomously downregulated in FOXG1 -/- dorsal telencephalic cells. We went on to show that the introduction into FOXG1 -/- embryos of a transgene designed to reverse Pax6 expression defects resulted in a partial rescue of the telencephalic progenitor proliferation defects. We conclude that FOXG1 exerts control over telencephalic progenitor proliferation by cell autonomous mechanisms that include the regulation of Pax6, which itself is known to regulate proliferation cell autonomously in a regional manner.
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the transcription factor FOXG1 regulates the competence of telencephalic cells to adopt subpallial fates in mice
Development, 2010Co-Authors: Martine Manuel, Ben Martynoga, John D West, John O Mason, David PriceAbstract:FOXG1 is required for development of the ventral telencephalon in the embryonic mammalian forebrain. Although one existing hypothesis suggests that failed ventral telencephalic development in the absence of FOXG1 is due to reduced production of the morphogens sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), the possibility that telencephalic cells lacking FOXG1 are intrinsically incompetent to generate the ventral telencephalon has remained untested. We examined the ability of FOXG1−/− telencephalic cells to respond to Shh and Fgf8 by examining the expression of genes whose activation requires Shh or Fgf8 in vivo and by testing their responses to Shh and Fgf8 in culture. We found that many elements of the Shh and Fgf8 signalling pathways continue to function in the absence of FOXG1 but, nevertheless, we were unable to elicit normal responses of key ventral telencephalic marker genes in FOXG1−/− telencephalic tissue following a range of in vivo and in vitro manipulations. We explored the development of FOXG1−/− cells in FOXG1−/− FOXG1+/+ chimeric embryos that contained ventral telencephalon created by normally patterned wild-type cells. We found that FOXG1−/− cells contributed to the chimeric ventral telencephalon, but that they retained abnormal specification, expressing dorsal rather than ventral telencephalic markers. These findings indicate that, in addition to regulating the production of ventralising signals, FOXG1 acts cell-autonomously in the telencephalon to ensure that cells develop the competence to adopt ventral identities.
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the winged helix transcription factor FOXG1 facilitates retinal ganglion cell axon crossing of the ventral midline in the mouse
Development, 2004Co-Authors: Thomas Pratt, John O Mason, Natasha M M L Tian, Ian T Simpson, David PriceAbstract:During normal development, retinal ganglion cells (RGCs) project axons along the optic nerve to the optic chiasm on the ventral surface of the hypothalamus. In rodents, most RGC growth cones then cross the ventral midline to join the contralateral optic tract; those that do not cross join the ipsilateral optic tract. Contralaterally projecting RGCs are distributed across the retina whereas ipsilaterally projecting RGCs are concentrated in temporal retina. The transcription factor FOXG1 (also known as BF1) is expressed at several key locations along this pathway. Analysis of FOXG1 expression using lacZ reporter transgenes shows that FOXG1 is normally expressed in most, if not all, nasal RGCs but not in most temporal RGCs, neither at the time they project nor earlier in their lineage. FOXG1 is also expressed at the optic chiasm. Mice that lack FOXG1 die at birth and, although the shape of their eyes is abnormal, their retinas still project axons to the brain via the optic chiasm. Using anterograde and retrograde tract tracing, we show that there is an eightfold increase in the ipsilateral projection in FOXG1-/- embryos. The distributions of cells expressing the transcription factors FOXG1 and Nkx2.2, and cell-surface molecules Ephb2, ephrin B2 and SSEA-1 (Fut4) have been correlated to the normally developing retinothalamic projection and we show they are not much altered in the developing FOXG1-/- retina and optic chiasm. As much of the increased ipsilateral projection in FOXG1-/- embryos arises from temporal RGCs that are unlikely to have an autonomous requirement for FOXG1, we propose that the phenotype reflects at least in part a requirement for FOXG1 outwith the RGCs themselves, most likely at the optic chiasm.
Prem Puri - One of the best experts on this subject based on the ideXlab platform.
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downregulation of forkhead box f1 gene expression in the pulmonary vasculature of nitrofen induced congenital diaphragmatic hernia
Pediatric Surgery International, 2016Co-Authors: J. Zimmer, T. Takahashi, A. D. Hofmann, Prem PuriAbstract:Purpose High mortality and morbidity in infants born with congenital diaphragmatic hernia (CDH) are attributed to pulmonary hypoplasia and pulmonary hypertension (PH). Forkhead box (Fox) transcription factors are known to be crucial for cell proliferation and homeostasis. FoxF1 is essential for lung morphogenesis, vascular development, and endothelial proliferation. Mutations in FoxF1 and also the Fox family member FoxC2 have been identified in neonates with PH. In human and experimental models of arterial PH, the Fox protein FoxO1 was found to be downregulated. We hypothesized that Fox expression is altered in the lungs of the nitrofen-induced CDH rat model and investigated the expression of FoxF1, FoxC2, and FoxO1.
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downregulation of forkhead box f1 gene expression in the pulmonary vasculature of nitrofen induced congenital diaphragmatic hernia
Pediatric Surgery International, 2016Co-Authors: J. Zimmer, T. Takahashi, A. D. Hofmann, Prem PuriAbstract:High mortality and morbidity in infants born with congenital diaphragmatic hernia (CDH) are attributed to pulmonary hypoplasia and pulmonary hypertension (PH). Forkhead box (Fox) transcription factors are known to be crucial for cell proliferation and homeostasis. FoxF1 is essential for lung morphogenesis, vascular development, and endothelial proliferation. Mutations in FoxF1 and also the Fox family member FoxC2 have been identified in neonates with PH. In human and experimental models of arterial PH, the Fox protein FoxO1 was found to be downregulated. We hypothesized that Fox expression is altered in the lungs of the nitrofen-induced CDH rat model and investigated the expression of FoxF1, FoxC2, and FoxO1. Following ethical approval (Rec 913b), time-pregnant Sprague–Dawley rats received nitrofen or vehicle on gestational day (D9). Fetuses were sacrificed on D21, inspected for CDH and divided into CDH (n = 11) and control group (n = 11). Gene expression of FoxF1, FoxC2, and FoxO1 was evaluated with qRT-PCR. Detected alterations of mRNA levels were subsequently assessed on the protein level by performing western blot analysis and laser scanning confocal microscopy. The relative mRNA level of FoxF1 was significantly downregulated in CDH lungs compared to controls (FoxF1 CDH 1.047 ± 0.108, FoxF1 Ctrl 1.419 ± 0.01, p = 0.014). Relative mRNA levels of FoxC2 and FoxO1 were not found to be altered between the experimental groups (FoxC2 CDH 30.74 ± 8.925, FoxC2 Ctrl 27.408 ± 7.487, p = 0.776; FoxO1 CDH 0.011 ± 0.002, FoxO1 Ctrl 0.011 ± 0.001, p = 0.809). On the protein level, western blotting demonstrated a reduced pulmonary protein expression of FoxF1 in CDH lungs. Confocal microscopy showed a markedly diminished expression of FoxF1 in the pulmonary vasculature of CDH lungs compared to controls. Our study demonstrates a strikingly reduced expression of FoxF1 in the pulmonary vasculature of nitrofen-induced CDH. Altered FoxF1 gene expression during embryogenesis may participate in vascular maldevelopment resulting in PH in this animal model.
Yuan Zhang - One of the best experts on this subject based on the ideXlab platform.
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knockdown of FOXG1 in sox9 supporting cells increases the trans differentiation of supporting cells into hair cells in the neonatal mouse utricle
Aging, 2020Co-Authors: Yuan Zhang, Chunjie Zhao, Shasha Zhang, Zhonghong Zhang, Ying Dong, Ruiying Qiang, Yin Chen, Xia Gao, Fangyi Chen, Renjie ChaiAbstract:FOXG1 plays important roles in regeneration of hair cell (HC) in the cochlea of neonatal mouse. Here, we used Sox9-CreER to knock down FOXG1 in supporting cells (SCs) in the utricle in order to investigate the role of FOXG1 in HC regeneration in the utricle. We found Sox9 an ideal marker of utricle SCs and bred Sox9CreER/+FOXG1loxp/loxp mice to conditionally knock down FOXG1 in utricular SCs. Conditional knockdown (cKD) of FOXG1 in SCs at postnatal day one (P01) led to increased number of HCs at P08. These regenerated HCs had normal characteristics, and could survive to at least P30. Lineage tracing showed that a significant portion of newly regenerated HCs originated from SCs in FOXG1 cKD mice compared to the mice subjected to the same treatment, which suggested SCs trans-differentiate into HCs in the FOXG1 cKD mouse utricle. After neomycin treatment in vitro, more HCs were observed in FOXG1 cKD mice utricle compared to the control group. Together, these results suggest that FOXG1 cKD in utricular SCs may promote HC regeneration by inducing trans-differentiation of SCs. This research therefore provides theoretical basis for the effects of FOXG1 in trans-differentiation of SCs and regeneration of HCs in the mouse utricle.
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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
Cellular and Molecular Life Sciences, 2020Co-Authors: Shasha Zhang, Yuan Zhang, Ying Dong, Lingna Guo, Zhong Zhang, Buwei Shao, Han Zhou, Weijie Zhu, Xiaoqian Yan, Guodong HongAbstract: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.
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the role of FOXG1 in the postnatal development and survival of mouse cochlear hair cells
Neuropharmacology, 2019Co-Authors: Yuan Zhang, Buwei Shao, Qiaojun Fang, Yuhua Zhang, Xiao Han, Rongrong GuoAbstract:Abstract The development of therapeutic interventions for hearing loss requires a detailed understanding of the genes and proteins involved in hearing. The FOXG1 protein plays an important role in early neural development and in a variety of neurodevelopmental disorders. Previous studies have shown that there are severe deformities in the inner ear in FOXG1 knockout mice, but due to the postnatal lethality of FOXG1 knockout mice, the role of FOXG1 in hair cell (HC) development and survival during the postnatal period has not been investigated. In this study, we took advantage of transgenic mice that have a specific knockout of FOXG1 in HCs, thus allowing us to explore the role of FOXG1 in postnatal HC development and survival. In the FOXG1 conditional knockout (CKO) HCs, an extra row of HCs appeared in the apical turn of the cochlea and some parts of the middle turn at postnatal day (P)1 and P7; however, these HCs gradually underwent apoptosis, and the HC number was significantly decreased by P21. Auditory brainstem response tests showed that the FOXG1 CKO mice had lost their hearing by P30. The RNA-Seq results and the qPCR verification both showed that the Wnt, Notch, IGF, EGF, and Hippo signaling pathways were down-regulated in the HCs of FOXG1 CKO mice. The significant down-regulation of the Notch signaling pathway might be the reason for the increased numbers of HCs in the cochleae of FOXG1 CKO mice at P1 and P7, while the down-regulation of the Wnt, IGF, and EGF signaling pathways might lead to subsequent HC apoptosis. Together, these results indicate that knockout of FOXG1 induces an extra row of HCs via Notch signaling inhibition and induces subsequent apoptosis of these HCs by inhibiting the Wnt, IGF, and EGF signaling pathways. This study thus provides new evidence for the function and mechanism of FOXG1 in HC development and survival in mice.
Buwei Shao - One of the best experts on this subject based on the ideXlab platform.
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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
Cellular and Molecular Life Sciences, 2020Co-Authors: Shasha Zhang, Yuan Zhang, Ying Dong, Lingna Guo, Zhong Zhang, Buwei Shao, Han Zhou, Weijie Zhu, Xiaoqian Yan, Guodong HongAbstract: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.
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the role of FOXG1 in the postnatal development and survival of mouse cochlear hair cells
Neuropharmacology, 2019Co-Authors: Yuan Zhang, Buwei Shao, Qiaojun Fang, Yuhua Zhang, Xiao Han, Rongrong GuoAbstract:Abstract The development of therapeutic interventions for hearing loss requires a detailed understanding of the genes and proteins involved in hearing. The FOXG1 protein plays an important role in early neural development and in a variety of neurodevelopmental disorders. Previous studies have shown that there are severe deformities in the inner ear in FOXG1 knockout mice, but due to the postnatal lethality of FOXG1 knockout mice, the role of FOXG1 in hair cell (HC) development and survival during the postnatal period has not been investigated. In this study, we took advantage of transgenic mice that have a specific knockout of FOXG1 in HCs, thus allowing us to explore the role of FOXG1 in postnatal HC development and survival. In the FOXG1 conditional knockout (CKO) HCs, an extra row of HCs appeared in the apical turn of the cochlea and some parts of the middle turn at postnatal day (P)1 and P7; however, these HCs gradually underwent apoptosis, and the HC number was significantly decreased by P21. Auditory brainstem response tests showed that the FOXG1 CKO mice had lost their hearing by P30. The RNA-Seq results and the qPCR verification both showed that the Wnt, Notch, IGF, EGF, and Hippo signaling pathways were down-regulated in the HCs of FOXG1 CKO mice. The significant down-regulation of the Notch signaling pathway might be the reason for the increased numbers of HCs in the cochleae of FOXG1 CKO mice at P1 and P7, while the down-regulation of the Wnt, IGF, and EGF signaling pathways might lead to subsequent HC apoptosis. Together, these results indicate that knockout of FOXG1 induces an extra row of HCs via Notch signaling inhibition and induces subsequent apoptosis of these HCs by inhibiting the Wnt, IGF, and EGF signaling pathways. This study thus provides new evidence for the function and mechanism of FOXG1 in HC development and survival in mice.
