دورية أكاديمية
COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors.
| العنوان: | COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors. |
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| المؤلفون: | Ferreira LGA; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.; Murdoch Children's Research Institute, Melbourne, Australia., Kizys MML; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Gama GAC; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Pachernegg S; Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, The University of Melbourne, Melbourne, Australia., Robevska G; Murdoch Children's Research Institute, Melbourne, Australia., Sinclair AH; Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, The University of Melbourne, Melbourne, Australia., Ayers KL; Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, The University of Melbourne, Melbourne, Australia., Dias-da-Silva MR; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. mrdsilva@unifesp.br. |
| المصدر: | Cell & bioscience [Cell Biosci] 2024 Jan 04; Vol. 14 (1), pp. 3. Date of Electronic Publication: 2024 Jan 04. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 101561195 Publication Model: Electronic Cited Medium: Print ISSN: 2045-3701 (Print) Linking ISSN: 20453701 NLM ISO Abbreviation: Cell Biosci Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: London : BioMed Central, 2011- |
| مستخلص: | Background: The absence of expression of the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) leads bipotential gonads into ovarian development. However, genetic variants in NR2F2, encoding three isoforms of the transcription factor COUP-TFII, represent a novel cause of SRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part of the ovarian developmental network. COUP-TFII is known to be expressed in interstitial/mesenchymal cells giving rise to steroidogenic cells in fetal gonads, however its expression and function in ESGCs have yet to be explored. Results: By differentiating induced pluripotent stem cells into bipotential gonad-like cells in vitro and by analyzing single cell RNA-sequencing datasets of human fetal gonads, we identified that NR2F2 expression is highly upregulated during bipotential gonad development along with markers of bipotential state. NR2F2 expression was detected in early cell populations that precede the steroidogenic cell emergence and that retain a multipotent state in the undifferentiated gonad. The ESGCs differentiating into fetal Sertoli cells lost NR2F2 expression, whereas pre-granulosa cells remained NR2F2-positive. When examining the NR2F2 transcript variants individually, we demonstrated that the canonical isoform A, disrupted by frameshift variants previously reported in 46,XX T/OT-DSD patients, is nearly 1000-fold more highly expressed than other isoforms in bipotential gonad-like cells. To investigate the genetic network under COUP-TFII regulation in human gonadal cell context, we generated a NR2F2 knockout (KO) in the human granulosa-like cell line COV434 and studied NR2F2-KO COV434 cell transcriptome. NR2F2 ablation downregulated markers of ESGC and pre-granulosa cells. NR2F2-KO COV434 cells lost the enrichment for female-supporting gonadal progenitor and acquired gene signatures more similar to gonadal interstitial cells. Conclusions: Our findings suggest that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that COUP-TFII regulates cell fate during gonad development and impairment of its function may disrupt the transcriptional plasticity of ESGCs. During early gonad development, disruption of ESGC plasticity may drive them into commitment to the testicular pathway, as observed in 46,XX OT-DSD patients with NR2F2 haploinsufficiency. (© 2023. The Author(s).) |
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| معلومات مُعتمدة: | 2021/00684-3 Fundação de Amparo à Pesquisa do Estado de São Paulo; 200262/2022-0 Conselho Nacional de Desenvolvimento Científico e Tecnológico |
| فهرسة مساهمة: | Keywords: 46,XX DSD; Bipotential gonad; COUP-TFII; Sex development; Supporting gonadal cells |
| تواريخ الأحداث: | Date Created: 20240104 Latest Revision: 20240108 |
| رمز التحديث: | 20240108 |
| مُعرف محوري في PubMed: | PMC10768475 |
| DOI: | 10.1186/s13578-023-01182-5 |
| PMID: | 38178246 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 2045-3701 |
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| DOI: | 10.1186/s13578-023-01182-5 |