Primordial germ cells (PGCs) are the only cell type capable of transmitting genetic information to the next generation. Following specification during early embryogenesis, PGCs undergo extensive migration before colonizing the developing gonads, where they ultimately give rise to sperm or oocytes. Although the molecular mechanisms governing PGC specification have been extensively investigated, how germ cell identity is stably maintained during migration with dramatically epigenetic reprogramming, has remained largely unknown.
In a study published in Cell Research, the team led by Prof. LI Jinsong from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences, in collaboration with Prof. LI Qing from Shanghai Jiao Tong University School of Medicine, Prof. ZHANG Man from Guangzhou National Laboratory, Prof. HU Ronggui from Zhejiang University School of Medicine, and Prof. ZHENG Hui from ShanghaiTech University, identified the E3 ubiquitin ligase TRIM37 as a key regulator that preserves primordial germ cell identity during migration.
To systematically identify regulators of PGC development, the researchers optimized their previously established semi-cloning-based in vivo genetic screening platform to enable rapid functional interrogation of candidate genes in mouse embryos. A targeted genetic screen of the TRIM family identified Trim37 whose disruption consistently caused PGC depletion without affecting early embryonic development. Multiple independent knockout and conditional knockout mouse models further demonstrated that TRIM37 is dispensable for PGC specification but is essential for maintaining germ cell identity during the migratory stage beginning at embryonic day 9.5 (E9.5).
Using single-cell RNA sequencing and lineage tracing strategies, the researchers found that loss of Trim37 resulted in progressive destabilization of germ cell identity. A subset of mutant PGCs deviated from the normal developmental trajectory, lost germline characteristics, and aberrantly activated mesodermal and other somatic developmental programs, indicating that TRIM37 is required to actively suppress inappropriate somatic gene expression during PGC migration.
Mechanistically, the study showed that TRIM37 directly interacts with TRIM28 through its MATH domain and ubiquitinates TRIM28 via its RING domain. This ubiquitination enhances the interaction between TRIM37 and TRIM28 and promotes nuclear retention of TRIM37. Disruption of the TRIM37–TRIM28 interaction, forced cytoplasmic localization of TRIM37, or loss of TRIM37 ubiquitin ligase activity all resulted in defective PGC maintenance. The researchers further identified lysine residues K774 and K779 of TRIM28 as critical ubiquitination sites required for normal germ cell development.
By integrating ATAC-seq, CUT&RUN, and CUT&Tag analyses, the researchers further demonstrated that TRIM37 deficiency reduced TRIM28 occupancy at numerous somatic developmental loci, accompanied by increased chromatin accessibility and elevated H3K27ac levels. Motif enrichment and functional analyses suggested that the transcription factor AP2γ cooperates with the TRIM37–TRIM28 complex to repress somatic transcriptional programs during PGC migration, thereby safeguarding germline identity.
Importantly, mouse models carrying Mulibrey nanism patient-associated TRIM37 mutations recapitulated the PGC defects observed in Trim37 knockout mice. Moreover, TRIM37, TRIM28, and AP2γ are co-expressed during human PGC development, suggesting that this regulatory network is evolutionarily conserved.
Together, this study establishes a TRIM37-TRIM28-AP2γ regulatory axis that actively safeguards primordial germ cell identity during migration. These findings provide new insights into the molecular mechanisms underlying germline fate maintenance and offer a conceptual framework for understanding reproductive disorders associated with germ cell developmental defects.
Reference: https://www.nature.com/articles/s41422-026-01272-2
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