title: Regenerative phenotype in mice with a point mutation in transforming growth factor beta type I receptor (TGFBR1).
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Victoria
authors.initials: V
authors.lastname: Piamonte
authors.forename: Brian M
authors.initials: BM
authors.lastname: Steffy
authors.forename: Mindy H
authors.initials: MH
authors.lastname: Hsieh
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ng
authors.forename: Jay
authors.initials: J
authors.lastname: Zhang
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.forename: Ken
authors.initials: K
authors.lastname: Muneoka
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D020219:Chondrogenesis; D005038:Ethylnitrosourea; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010641:Phenotype; D010766:Phosphorylation; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D012038:Regeneration; D051899:Smad2 Protein / Q000378:metabolism; D014945:Wound Healing
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse; D005038:Ethylnitrosourea