Tmsb10 triggers fetal Leydig differentiation by suppressing the RAS/ERK pathway

Inoue, Miki; Baba, Takashi; Takahashi, Fumiya; Terao, Miho; Yanai, Shogo; Shima, Yuichi; Saito, Daisuke; Sugihara, Kei; Miura, Takashi; Takada, Shuji; Suyama, Mikita; Ohkawa, Yasuyuki; Morohashi, Ken-ichirou

doi:10.1038/s42003-022-03941-5

Cited by 4 publications

(2 citation statements)

References 79 publications

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“…Te upregulation of TMSB10 in glioma tissues compared to normal brain tissues provides valuable insights into its involvement in glioma pathogenesis. TMSB10 belongs to the family of β-thymosins, which are involved in various cellular processes, including actin dynamics, cell motility, and cytoskeletal organization [5,15]. Te physiological functions of TMSB10 in the brain are not fully understood, but its upregulation in glioma suggests its potential contribution to tumor development and progression [16].…”

Section: Discussionmentioning

confidence: 99%

The Clinical Relevance and Functional Implications of Thymosin Beta-10 in Glioma

Li,

Chen,

Xiang

et al. 2023

Genetics Research

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Glioma is a highly aggressive form of brain cancer characterized by limited treatment options and poor patient prognosis. In this study, we aimed to elucidate the oncogenic role of thymosin beta-10 (TMSB10) in glioma through comprehensive analyses of patient data from the TCGA and GTEx databases. Our investigation encompassed several key aspects, including the analysis of patients’ clinical characteristics, survival analysis, in vitro and in vivo functional experiments, and the exploration of correlations between TMSB10 expression and immune cell infiltration. Our findings revealed a significant upregulation of TMSB10 expression in glioma tissues compared to normal brain tissues, with higher expression levels observed in tumors of advanced histological grades. Moreover, we observed positive correlations between TMSB10 expression and patient age, while no significant association with gender was detected. Additionally, TMSB10 exhibited marked elevation in gliomas with wild-type IDH and noncodeletion of 1p/19q. Survival analysis indicated that high TMSB10 expression was significantly associated with worse overall survival, disease-specific survival, and progression-free survival in glioma patients. Functionally, knockdown of TMSB10 in glioma cells resulted in reduced cellular growth rates and impaired tumor growth in xenograft models. Furthermore, our study revealed intriguing correlations between TMSB10 expression and immune cell infiltration within the tumor microenvironment. Specifically, TMSB10 showed negative associations with plasmacytoid dendritic cells (pDC) and γδ T cells (Tgd), while displaying positive correlations with neutrophils and macrophages. These findings collectively provide valuable insights into the oncogenic properties of TMSB10 in glioma, suggesting its potential as a therapeutic target and a biomarker for patient stratification.

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Section: Discussionmentioning

confidence: 99%

The Clinical Relevance and Functional Implications of Thymosin Beta-10 in Glioma

Li,

Chen,

Xiang

et al. 2023

Genetics Research

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“…Desert Hedgehog (DHH) secreted by Sertoli cells acts on the interstitial progenitors expressing the Hedgehog receptor Patched1 (PTCH1) and the Hedgehog effectors GLI1, 2 and 3 to trigger FLC and PTM differentiation (20)(21)(22)(23)(24)(25)(26). In addition FLC development requires the activation of signaling pathways downstream of PDGFRA in the steroidogenic progenitors (27)(28)(29). On the other hand, ligands present in vascular and peri-vascular cells activate NOTCH2 receptor and the expression of the effectors HES1 and HEYL in interstitial progenitors to maintain their undifferentiated state and restrict FLC formation (18,(30)(31)(32).…”

Section: Figures S1 To S5mentioning

confidence: 99%

NR2F2 is required in the embryonic testis for Fetal Leydig Cell development

Perea-Gomez,

Bellido-Carreras,

Dhellemmes

et al. 2024

Preprint

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Male genital development in XY mammalian fetuses is triggered by the action of hormones, including testosterone, secreted by the developing testes. Defects in this process are a cause for Differences in Sex Development (DSD), one of the most common congenital abnormalities in humans. Fetal Leydig Cells (FLC) play a central role for the synthesis of masculinizing hormones in the developing testes. Yet, the genetic cascade controlling their differentiation is poorly understood. Here we investigate the role of the orphan nuclear receptor NR2F2 in FLC development. We report that NR2F2 is expressed in interstitial progenitor cells of the mouse embryonic testes and is downregulated upon their differentiation into FLC. By using two mouse models for conditional mutation of Nr2f2 in the developing testes we demonstrate that NR2F2 is required for testis morphogenesis and FLC development. NR2F2 acts in interstitial progenitors to regulate the initiation and progression of FLC differentiation independently of paracrine signaling pathways known to control this process. These results establish NR2F2 as an essential regulator of FLC development and steroid hormone synthesis in the mouse fetal testis and provide an entry point to understand the etiology of 46, XY DSD associated to pathogenic NR2F2 variants.

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Expression patterns of sex steroid receptors in developing mesonephros of the male mouse: three-dimensional analysis

et al. 2023

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The androgen pathway via androgen receptor (AR) has received the most attention for development of male reproductive tracts.The estrogen pathway through estrogen receptor (ESR1) is also a major contributor to rete testis and efferent duct formation, but the role of progesterone via progesterone receptor (PGR) has largely been overlooked. Expression patterns of these receptors in the mesonephric tubules (MTs) and Wol an duct (WD), which differentiate into the efferent ductules and epididymis, respectively, remain unclear because of the di culty in distinguishing each region of the tracts. This study investigated AR, ESR1, and PGR expressions in the murine mesonephros using three-dimensional (3-D) reconstruction. The receptors were localized in serial para n sections of the mouse testis and mesonephros by immunohistochemistry on embryonic days (E) 12.5, 15.5, and 18.5. Speci c regions of the developing MTs and WD were determined by 3-D reconstruction using Amira software. AR was found rst at the distal end (gonadal side) of MTs at E12.5, and the epithelial expression showed increasing strength from cranial to the caudal side. Epithelial expression of ESR1 was found in the cranial WD and MTs near the WD rst at E15.5. PGR was weakly positive only in the MTs and cranial WD starting on E15.5 but negative in the distal end of the MTs. This 3-D analysis suggests that gonadal androgen acts rst on the distal end of MTs but that estrogen is the rst to in uence MTs on the WD side, while potential PGR activity is delayed and limited to the epithelium.

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Tmsb10 triggers fetal Leydig differentiation by suppressing the RAS/ERK pathway

Cited by 4 publications

References 79 publications

The Clinical Relevance and Functional Implications of Thymosin Beta-10 in Glioma

The Clinical Relevance and Functional Implications of Thymosin Beta-10 in Glioma

NR2F2 is required in the embryonic testis for Fetal Leydig Cell development

Expression patterns of sex steroid receptors in developing mesonephros of the male mouse: three-dimensional analysis

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