Divergent roles of Smad1 and Smad2 in patterning the early mammalian embryo. (360G-Wellcome-099840_Z_12_Z)
The TGF? secreted growth factors bone morphogenetic protein (BMP) and nodal play crucial roles in cell fate specification during vertebrate gastrulation. BMPs, acting via Smad1/5/8 induce 'posterior' or extra-embryonic mesoderm (including the germ cell lineage), whereas nodal signals through Smad2/3 specify the 'anterior' primitive streak and its derivatives. Genetic studies in mice suggest that dose-dependent signaling via Smad1/5/8 and Smad2/3 plays complementary roles in regulating cell fate allocation during gastrulation. Ablation of Smad1 primarily disrupts specification of extra-embryonic mesodermand formation of the germ cell lineage, whereas Smad2 functional loss results in defective gastrulation and enhanced formation of extra-embryonic mesoderm. The underlying causes of these complex tissue disturbances remain ill-defined.Information about Smad-regulated transcripts in the embryo is missing. To identify downstream Smad transcriptional targets, Smad1 and Smad2 mutant embryos will be characterized using a new panel of tissue-specific marker genes and profiled by microarrays and RNA-seq. These in vivo experiments will be complemented by investigation of the differentiation potential of mutant embryonic stem (ES) cells towards distinct cell fates in vitro. The transcriptional networks downstream of Smad1 and Smad2 in the early mammalian embryo also govern human development and disease.
£159,340 16 Jul 2012