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| Status |
Public on Nov 02, 2023 |
| Title |
FGF independent MEK1/2 signalling is essential for male germline development in mice [germ cell] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Germline 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. Inhibition 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 the germ cells entered mitotic arrest normally. While male germline development was not disrupted by FGF inhibition, a significant number of 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. Together, these data demonstrate a novel and essential role for MEK1/2 signalling in male germline differentiation, but a surprisingly 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.
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| Overall design |
E12.5 testes or ovaries were cultured for 0, 24 or 72h with DMSO (vehicle control), BGJ398 (FGFRi) or PD0325901 (MEKi). Several gonads were pooled for 1 biological replicate and germ cell populations were isolated via FACS. 4 biological replicates were analysed for each treatment.
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| Contributor(s) |
Blücher RO, Lim RS, Jarred EG, Ritchie ME, Western PS |
| Citation(s) |
38053127 |
| Submission date |
Dec 20, 2022 |
| Last update date |
Dec 14, 2023 |
| Contact name |
Matthew Ritchie |
| E-mail(s) |
mritchie@wehi.edu.au
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| Organization name |
The Walter and Eliza Hall Institute of Medical Research
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| Department |
Epigenetics and Development Division
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| Street address |
1G Royal Parade
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| City |
Parkville |
| State/province |
Victoria |
| ZIP/Postal code |
3052 |
| Country |
Australia |
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| Platforms (1) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA914327 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE221453_germ_gene_counts.tsv.gz |
1.3 Mb |
(ftp)(http) |
TSV |
| GSE221453_germ_sample_barcodes.txt.gz |
625 b |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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