Genes Genomics 2025 Jun 16; doi: 10.1007/s13258-025-01654-7.

Foxj3 represses TGF-β signals-responsive transcriptions in Xenopus early development.

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BACKGROUND: Forkhead box (Fox) proteins belong to a large family of transcription factors characterized by a highly conserved DNA binding domain termed the 'forkhead box'. They are involved in critical functions during early development and in the adult. OBJECTIVE: In this work, Foxj3 was found to regulate negatively the transcription of target genes induced by Activin/Nodal or BMP signal in Xenopus embryos. Thus, we sought to investigate the molecular mechanisms underlying this function of Foxj3 as a transcriptional repressor. METHODS: Microinjection of mRNA and anti-sense morpholino oligo was employed to achieve the gain- and loss-of Foxj3 function, respectively. RT-PCR and luciferase assays were performed to investigate the effects of overexpression or knockdown of Foxj3 on TGF-β signals-responsive transcriptions. Animal cap elongation assay was used to check whether Foxj3 would affect the dorsalization of ectodermal tissues induced by Activin signal. Whole-mount in situ hybridization was carried out to analyze the in vivo expression of key marker genes in the embryos overexpressing or depleted of Foxj3. RESULTS: Overexpression of Foxj3 was found to repress the gene responses activated by Activin/Nodal or BMP4 signals. Its increased levels also caused defective mesodermal and ectodermal specification in embryo. Conversely, knockdown of Foxj3 augmented Nodal-responsive transcription of target genes. In line with this, Foxj3 morphants displayed the malformed phenotypes resembling those of embryos exposed to increased levels of Nodal signal. Furthermore, Foxj3 repression of transcriptional responses was blocked by depletion of RNF152 or co-expression of β-catenin. CONCLUSION: Foxj3 functions via the RNF152/β-catenin signaling axis to repress TGF-β-dependent transcriptional responses in Xenopus early development.

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