Biology subjects

Jarred, E. G.

Publications and source records attributed to Jarred, E. G..

2 recordsLinked to original sources

bioRxiv2023

FGF independent MEK1/2 signalling is essential for male germline development in mice

BackgroundGermline development provides the founding cells for spermatogenesis and oogenesis in males and females, respectively. Disrupted germline differentiation or compromised testis development can lead to subfertility or infertility and are strongly associated with testis cancer in humans. In mice, SRY and SOX9 induce expression of a range of genes, including Fgf9, that promote Sertoli cell differentiation and testis development. FGF9 is also thought to promote male germline differentiation but the pathway through which it signals is unknown. As FGFs signal through Mitogen-Activated Protein Kinases (MAPKs) in other tissues, we explored whether FGF9 regulates male germline development through MAPK by inhibiting either FGF or MEK1/2 signalling in fetal testis cultures from embryonic day (E)12.5, immediately after gonadal sex determination and testis cord formation, but prior to male germline commitment. ResultsInhibition of MEK1/2 disrupted mitotic arrest, dysregulated a broad range of male germline development genes and prevented the upregulation of key male germline markers DPPA4 and DNMT3L. In contrast, when FGF signalling was inhibited, the male germline specific transcriptional program and the expression of male germline markers DPPA4 and DNMT3L were unaffected, and germ cells entered mitotic arrest normally. While male germline development was not disrupted by FGF inhibition, some genes were commonly altered after 24h of FGF or MEK1/2 inhibition including genes involved in maintenance, germline stem cells, Nodal signalling, proliferation, and germline cancer. ConclusionsTogether, these data demonstrate a novel and essential role for MEK1/2 signalling in male germline differentiation, but a more limited role for FGF signalling. Our data strongly indicate that additional ligands act through MEK1/2 to promote male germline differentiation and highlight a need for further mechanistic understanding of male germline development.

developmental biology↗

bioRxiv2022

Transient Polycomb activity represses developmental genes in growing oocytes.

BackgroundNon-genetic disease inheritance and offspring phenotype is substantially influenced by germline epigenetic programming, including genomic imprinting. Loss of Polycomb Repressive Complex 2 (PRC2) function in oocytes causes non-genetically inherited effects on offspring, including embryonic growth restriction followed by post-natal offspring overgrowth. While PRC2 dependent non-canonical imprinting is likely to contribute, less is known about germline epigenetic programming of non-imprinted genes during oocyte growth. In addition, de novo germline mutations in genes encoding PRC2 lead to overgrowth syndromes in human patients, but the extent to which PRC2 activity is conserved in human oocytes is poorly understood. ResultsIn this study we identify a discrete period of early oocyte growth during which PRC2 is expressed in mouse growing oocytes. Deletion of Eed during this window led to the de-repression of 343 genes. A high proportion of these were developmental regulators, and the vast majority were not imprinted genes. Many of the de-repressed genes were also marked by the PRC2-dependent epigenetic modification histone 3 lysine 27 trimethylation (H3K27me3) in primary-secondary mouse oocytes, at a time concurrent with PRC2 expression. In addition, we found H3K27me3 was also enriched on many of these genes by the germinal vesicle (GV) stage in human oocytes, strongly indicating that this PRC2 function is conserved in the human germline. However, while the 343 genes were de-repressed in mouse oocytes lacking EED, they were not de-repressed in pre-implantation embryos and lost H3K27me3 during pre-implantation development. This implies that H3K27me3 is a transient feature that represses a wide range of genes in oocytes. ConclusionsTogether, these data indicate that EED has spatially and temporally distinct functions in the female germline to repress a wide range of developmentally important genes, and that this activity is conserved in the mouse and human germlines.

developmental biology↗