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Characterization of Tgfbm2 , a genetic modifier of Tgfb1 −/− embryonic lethality.
Author(s) -
Clermont Frederic,
Luu Minh Thu,
Higgins Mamie,
Akhurst Rosemary J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb73-b
Subject(s) - biology , congenic , gene , genetics , phenotype , penetrance , allele , candidate gene , embryo , null allele , gene targeting , microbiology and biotechnology
TGFβ1 is required for developmental angiogenesis and vascular integrity as demonstrated by the phenotypes of both humans and mice with null mutations in components of the TGFβ1 signaling pathway. However the phenotypic penetrance is variable in both humans and mice. The objective of this work is to identify genes that confer redundancy for Tgfb1 during vascular development. Tgfb1 −/− C57BL/6J (C57) embryos invariably die in utero around 10.5dpc, due to defective development of the vascular system. However, three variant genetic loci from other mouse strains (termed Tgfbm1‐3 ) have been identified that suppress a requirement for Tgfb1 during vascular development. In the present study, we present progress towards validation and characterization of the genetic modifier gene(s) within Tgfbm2. The Tgfbm2 129 allele, bred onto either the C57 or NIH genetic background, rescues Tgfb1 −/− mice from embryo lethality. Phenotyping of C57 Tgfbm2 129 congenic mice has been used to definitively map the Tgfbm2 modifier effect to <1Mb harboring only 4 genes ( Kctd3 , Kcnk2 , Cenpf and Ptpn14 ). Sequencing of the coding region of all four genes reveals synonymous as well as non‐synonymous nucleotide polymorphisms between the C57 and 129 mouse strains. Expression analysis, functional investigation of the four candidate genes, and how they interact with the TGFβ1 signaling pathway both in vitro and in vivo , will be presented.