Regulatory Role of Trim33 in Morphogenesis: A Paradigm for Common Human Congenital Defects

[摘要] Transforming Growth Factor – beta signaling plays important, pleiotropic roles in embryonic development as well as tissue homeostasis. TGF-beta signaling dose is tightly regulated in a context-specific manner and even subtle perturbations result in a spectrum of disease phenotypes of varying severity. In the canonical TGF-beta pathway, TGF-beta signals are mediated by activated receptor-regulated Smads (R-Smads, Smad2/3) that form a complex with Smad4 and participate in transcriptional regulation of TGF-beta-mediated genes with sequence specific DNA binding factors and context-specific co-regulators. Both Smad2/3 and Smad4 regulate signal duration and intensity differentially. This is consistent with the variability and spectrum of phenotypes observed upon their conditional deletions in mice, with Smad2/3-associated phenotypes being more severe than those associated with Smad4.However, precise mechanisms that modulate the functional and phenotypic differences attributed to Smad2/3 and Smad4 are poorly understood. Tripartite motif containing (Trim) 33 - a co-regulator of both activated Smad2/3 and Smad4, is a candidate gene for understanding fine tuning mechanisms of TGF-beta signaling. Here, I have investigated the role of Trim33 in early embryogenesis. My results show that Trim33 controls visceral endoderm differentiation in vitro and pre-cardiac mesoderm differentiation in vivo. Epiblast-specific Trim33 mutants die during the second half of gestation as a result of ensuing cardiac failure. My findings imply that Trim33 is required for appropriate early mesendoderm differentiation soon after its induction, regulates TGF-beta superfamily signaling in a biphasic manner in the pre-cardiac mesoderm, and that in more committed cell lineages Trim33 is dispensable.

[发布机构] University of Michigan

[效力级别] embryonic stem cell

[关键词] Cardiac;embryonic stem cell;morphogenesis;embryogenesis;Trim33;TGF-beta;Molecular;Cellular and Developmental Biology;Health Sciences;Oral Health Sciences