Biology subjects

Dupont, S. M.

Publications and source records attributed to Dupont, S. M..

2 recordsLinked to original sources

bioRxiv2025

The basic helix-loop-helix transcription factor TCF4 recruits the Mediator Complex to activate gonadal genes and drive ovarian development

The bipotential gonad is the precursor organ to both the ovary and testis and develops as part of the embryonic urogenital system. In mice, gonadogenesis initiates around embryonic day 9.5 (E9.5), when coelomic epithelial (CE) cells overlaying the mesonephric ducts proliferate and acquire competence to differentiate into the somatic cell types of the embryonic gonad, the pre-supporting cell (Sertoli cells in the testis and granulosa cells in the ovary) and the interstitial cell lineages. While some transcription factors that drive gonadal cell fate are known, we found that basic helix-loop-helix (bHLH) binding sites are highly represented upstream of granulosa and interstitial genes. We investigated the bHLH Transcription Factor 4 (TCF4), which is expressed in GATA4+ somatic cells in both sexes prior to sex determination, maintained in ovarian pre-supporting cells and interstitial cells of both sexes, but silenced specifically in male pre-supporting cells. In a Tcf4STOP/STOP mutant mouse model that lacks the TCF4 DNA-binding domain, we found that the marker of Sertoli fate, SOX9, was higher in Sertoli cells, while markers of granulosa and interstitial fate (FOXL2 and NR2F2) were reduced and the supporting to interstitial cell ratio was altered in XX Tcf4STOP/STOP ovaries. We found that TCF4 binds the Mediator complex and chromatin remodelers to regulate expression of Jun and other genes in early somatic cells. Collectively, these results support the working hypothesis that TCF4 regulates a gonadal program that primes the gonad towards a female fate but is specifically silenced in male supporting cells as the testis pathway diverges. Significant FindingsO_LIbHLH binding sites are more abundant in genes involved in sex-determination than SOX9 or FOXL2 sites, and are 1.5 times more common upstream of granulosa than Sertoli genes. C_LIO_LITCF4 is a Class I bHLH factor that is expressed in early gonadal progenitors, but silenced in Sertoli cells. C_LIO_LILoss of the TCF4 binding domain results in higher levels of SOX9, suggesting that TCF4 antagonizes the Sertoli pathway. C_LIO_LILoss of TCF4 binding domain reduces levels of FOXL2 and NR2F2 and leads to defects in ovary development. C_LIO_LITCF4 binds with all proteins in the Mediator complex to alter the transcriptional/epigenetic landscape which may explain how it functions on target genes such as Jun. C_LIO_LIOur findings identify Tcf4 as a potential upstream factor that skews the bipotential supporting cell lineage towards a granulosa cell fate. C_LI

developmental biology↗

bioRxiv2024

Global overview of sea turtle fibropapillomatosis tumors: a survey of expert opinions and trends.

Marine environments offer a wealth of opportunities to improve understanding and treatment options for cancers, through insights into a range of fields from drug discovery to mechanistic insights. By applying One Health principles the knowledge obtained can benefit both human and animal populations, including marine species suffering from cancer. One such species is green sea turtles (Chelonia mydas), which are under threat from fibropapillomatosis (FP), an epizootic tumor disease (animal epidemic) that continues to spread and increase in prevalence globally. In order to effectively address this epizootic, a more thorough understanding is required of the prevalence of the disease and the approaches to treating afflicted turtles. To identify knowledge gaps and assess future needs, we conducted a survey of sea turtle FP experts. The survey consisted of 47 questions designed to assess general perceptions of FP, the areas where more information is needed, local FP trends, the disease status, and mitigation needs, and was voluntarily completed by 44 experts across a broad geographic range. The survey responses provided a valuable overview of the current FP status in sea turtles, FP research, and insight into the approaches currently taken by turtle rehabilitation facilities around the world. Over 70% of respondents both recognized FP as a cancerous panzootic disease, and reported that FP is increasing in prevalence. They report several factors contributing to this increase. Nearly all of the respondents reported that FP research, patient treatment and rehabilitation required more funding in their area, and reported inadequate facilities and capacity for dealing with FP patients. Treatment approaches varied: just over 70% of the medical experts that responded surgically remove FP tumors, either using laser or scalpel. Just under half of respondents use anti-cancer drugs in their treatment of FP. Internal tumors were reported as justification for euthanasia by 61.5% of respondents, and 30.8% reported severe external tumors to be sufficient grounds for euthanasia. Most medical respondents (93.3%) routinely perform necropsy on deceased or euthanized FP-afflicted turtles. Over 80% of respondents considered large-scale multidisciplinary collaboration extremely important for advancing the field of FP research. The survey responses provide a valuable insight into the current state of FP treatment, rehabilitation and research, and help to identify critical FP-related research and rehabilitation areas most in need of attention.

cancer biology↗