Differential Inhibition of Sox10 Functions by Notch-Hes Pathway

Xiao, Guanxiu; Du, Junqing; Wu, Huihui; Ge, Xinqi; Xu, Xiaofeng; Yang, Adeline; Zhu, Ying; Hu, Xuemei; Zheng, Kang; Zhu, Qiang; Qiu, Mengsheng

doi:10.1007/s10571-019-00764-7

Cited by 9 publications

(5 citation statements)

References 37 publications

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“…We detected the significant promotion of NOTCH3 expression in FOXP4‐suppressed W12 cells by microarray and WAD ranking methods. 23 Although it has been reported that NOTCH3 expression is induced by ELF3 transcription factor 32 and promotes the expression of the HES family, 33 there has been no report describing the possible relationship between HPV‐impaired squamous differentiation and FOXP4. 3 This study first showed that ELF3 is involved in FOXP4‐dependent pathways to suppress squamous differentiation and suggests suppressive roles for ELF3 and NOTCH3 in CIN progression.…”

Section: Discussionmentioning

confidence: 99%

FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3‐dependent pathway

et al. 2022

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Although the human papillomavirus (HPV) vaccine is effective for preventing cervical cancers, this vaccine does not eliminate pre‐existing infections, and alternative strategies have been warranted. Here, we report that FOXP4 is a new target molecule for differentiation therapy of cervical intraepithelial neoplasia (CIN). An immunohistochemical study showed that FOXP4 was expressed in columnar epithelial, reserve, and immature squamous cells, but not in mature squamous cells of the normal uterine cervix. In contrast with normal mature squamous cells, FOXP4 was expressed in atypical squamous cells in CIN and squamous cell carcinoma lesions. The FOXP4‐positive areas significantly increased according to the CIN stages from CIN1 to CIN3. In monolayer cultures, downregulation of FOXP4 attenuated proliferation and induced squamous differentiation in CIN1‐derived HPV 16‐positive W12 cells via an ELF3‐dependent pathway. In organotypic raft cultures, FOXP4‐downregulated W12 cells showed mature squamous phenotypes of CIN lesions. In human keratinocyte‐derived HaCaT cells, FOXP4 downregulation also induced squamous differentiation via an ELF3‐dependent pathway. These findings suggest that downregulation of FOXP4 inhibits cell proliferation and promotes the differentiation of atypical cells in CIN lesions. Based on these results, we propose that FOXP4 is a novel target molecule for nonsurgical CIN treatment that inhibits CIN progression by inducing squamous differentiation.

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Section: Discussionmentioning

confidence: 99%

FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3‐dependent pathway

et al. 2022

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“…Transcription factor ELF3 was reported to induce expression of NOTCH3 25 and the HES family 26 . Somatic mutation or reduced expression of ELF3 was reported in uterine cervical adenocarcinomas, 27 urothelial bladder carcinoma, 28 and oral SCC 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Transcription factor ELF3 was reported to induce expression of NOTCH3 25 and the HES family. 26 Somatic mutation or reduced expression of ELF3 was reported in uterine cervical adenocarcinomas, 27 urothelial bladder carcinoma, 28 and oral SCC. 29 We previously showed that the downregulation of FOXP4 induced squamous differentiation in W12 cells via an ELF3‐dependent pathway.…”

Section: Discussionmentioning

confidence: 99%

Androgen promotes squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3‐dependent pathway

et al. 2023

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Background Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression. Methods Since AR expression was negative in W12 cells and HaCaT cells, a human male skin‐derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions. Results DHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR‐transfected W12 cells. Si‐RNA treatments showed that DHT induced the expression of squamous differentiation‐related genes in AR‐transfected W12 cells via an ELF3‐dependent pathway. DHT also reduced FOXP4 expression in AR‐transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN. Conclusion Androgen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone‐induced differentiation therapy against CIN1 and CIN2.

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“…Hes5 acts as an effector molecule in the Notch signaling pathway, which inhibits OL differentiation and myelination by repressing the expression of myelin genes and interacting with other transcription factors, such as Mash1 and Sox10 [ 23 ]. Similar to the role of PDGFRα in OPCs, Hes5 expression decreases during OPC differentiation, and its overexpression can prevent this process [ 50 ]. Previous research has indicated that the Notch signaling pathway plays a crucial role in various stages of generating mature, myelinating OLs [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development

Cao,

Sun,

Shen

et al. 2023

IJMS

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FOXG1 (forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the Foxg1 gene that affect brain structure and function. Individuals affected by FOXG1 syndrome frequently exhibit delayed myelination in neuroimaging studies, which may impair the rapid conduction of nerve impulses. To date, the specific effects of FOXG1 on oligodendrocyte lineage progression and myelination during early postnatal development remain unclear. Here, we investigated the effects of Foxg1 deficiency on myelin development in the mouse brain by conditional deletion of Foxg1 in neural progenitors using NestinCreER;Foxg1fl/fl mice and tamoxifen induction at postnatal day 0 (P0). We found that Foxg1 deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30. We also found that Foxg1 deletion prevented the timely attenuation of platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, Foxg1 deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results reveal the important role of Foxg1 in myelin development and provide new clues for further exploring the pathological mechanisms of FOXG1 syndrome.

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Differential Inhibition of Sox10 Functions by Notch-Hes Pathway

Cited by 9 publications

References 37 publications

FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3‐dependent pathway

FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3‐dependent pathway

Androgen promotes squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3‐dependent pathway

Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development

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