| First Author | Rodríguez A | Year | 2022 |
| Journal | PLoS Genet | Volume | 18 |
| Issue | 11 | Pages | e1010459 |
| PubMed ID | 36441774 | Mgi Jnum | J:331871 |
| Mgi Id | MGI:7407727 | Doi | 10.1371/journal.pgen.1010459 |
| Citation | Rodriguez A, et al. (2022) TGFbeta pathway is required for viable gestation of Fanconi anemia embryos. PLoS Genet 18(11):e1010459 |
| abstractText | Overexpression of the TGFbeta pathway impairs the proliferation of the hematopoietic stem and progenitor cells (HSPCs) pool in Fanconi anemia (FA). TGFbeta promotes the expression of NHEJ genes, known to function in a low-fidelity DNA repair pathway, and pharmacological inhibition of TGFbeta signaling rescues FA HSPCs. Here, we demonstrate that genetic disruption of Smad3, a transducer of the canonical TGFbeta pathway, modifies the phenotype of FA mouse models deficient for Fancd2. We observed that the TGFbeta and NHEJ pathway genes are overexpressed during the embryogenesis of Fancd2-/- mice and that the Fancd2-/-Smad3-/- double knockout (DKO) mice undergo high levels of embryonic lethality due to loss of the TGFbeta-NHEJ axis. Fancd2-deficient embryos acquire extensive genomic instability during gestation which is not reversed by Smad3 inactivation. Strikingly, the few DKO survivors have activated the non-canonical TGFbeta-ERK pathway, ensuring expression of NHEJ genes during embryogenesis and improved survival. Activation of the TGFbeta-NHEJ axis was critical for the survival of the few Fancd2-/-Smad3-/- DKO newborn mice but had detrimental consequences for these surviving mice, such as enhanced genomic instability and ineffective hematopoiesis. |
