Regenerative phenotype in mice with a point mutation in transforming growth factor β type I receptor (TGFBR1)

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 35; pp. 14560 - 14565
• Main Authors: Liu, Jun, Johnson, Kristen, Li, Jie, Piamonte, Victoria, Steffy, Brian M., Hsieh, Mindy H., Ng, Nicholas, Zhang, Jay, Walker, John R., Ding, Sheng, Muneoka, Ken, Wu, Xu, Glynne, Richard, Schultz, Peter G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.08.2011; National Acad Sciences
• Subjects: Amino Acid Sequence; Animals; Biological Sciences; Blood cells; Cartilage; Cell Differentiation; Chondrogenesis; Ethylnitrosourea; Genetic mutation; Healing; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Sequence Data; Phenotype; Phenotypes; Phenotypic traits; Phosphorylation; Point Mutation; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - physiology; Receptors; Receptors, Transforming Growth Factor beta - chemistry; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - physiology; Regeneration; Smad2 Protein - metabolism; Wound Healing
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1111056108

Regeneration of peripheral differentiated tissue in mammals is rare, and regulators of this process are largely unknown. We carried out a forward genetic screen in mice using N-ethyl-N-nitrosourea mutagenesis to identify genetic mutations that affect regenerative healing in vivo. More than 400 pedigrees were screened for closure of a through-and-through punch wound in the mouse ear. This led to the identification of a single pedigree with a heritable, fast, and regenerative wound-healing phenotype. Within 5 wk after ear-punch, a threefold decrease in the diameter of the wound was observed in the mutant mice compared with the wild-type mice. At 22 wk, new cartilage, hair follicles, and sebaceous glands were observed in the newly generated tissue. This trait was mapped to a point mutation in a receptor for TGF-β, TGFBR1. Mouse embryonic fibroblasts from the affected mice had increased expression of a subset of TGF-β target genes, suggesting that the mutation caused partial activation of the receptor. Further, bone marrow stromal cells from the mutant mice more readily differentiated to chondrogenic precursors, providing a plausible explanation for the enhanced development of cartilage islands in the regenerated ears. This mutant mouse strain provides a unique model to further explore regeneration in mammals and, in particular, the role of TGFBR1 in chondrogenesis and regenerative wound healing.