TGFβ pathway is required for viable gestation of Fanconi anemia embryos
Abstract
Overexpression of the TGFβ pathway impairs the proliferation of the hematopoietic stem and progenitor cells (HSPCs) pool in Fanconi anemia (FA). TGFβ promotes the expression of NHEJ genes, known to function in a low-fidelity DNA repair pathway, and pharmacological inhibition of TGFβ signaling rescues FA HSPCs. Here, we demonstrate that genetic disruption of Smad3, a transducer of the canonical TGFβ pathway, modifies the phenotype of FA mouse models deficient for Fancd2. We observed that the TGFβ 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 TGFβ-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 TGFβ-ERK pathway, ensuring expression of NHEJ genes during embryogenesis and improved survival. Activation of the TGFβ-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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 28, 2022
- Source ID
- 10.1371/journal.pgen.1010459
Entities
People
- Alan D'Andrea
- Alfredo Rodríguez
- Cecilia Ayala-zambrano
- Chunyu Yang
- David B. Martignetti
- Divya Ramalingam Iyer
- Eli Lilly
- Ha-Thanh Nguyen
- Jessica Filiatrault
- Joel S. Greenberger
- Kalindi Parmar
- Kelsey Mcqueen
- Larissa A. Sambel
- Martha Velázquez
- Michael Epperly
- Renee Fisher
- Sara Frías
- Ulises Juárez
Organizations
- DGAPA, UNAM
- Fanconi Anemia Research Fund
- Foundation for the National Institutes of Health
- Grayson-Jockey Club Research Foundation
- Richard and Susan Smith Family Foundation
- The Breast Cancer Research Foundation
- United States Department of Defense