Interaction Domains of Sos1/Grb2 Are Finely Tuned for Cooperative Control of Embryonic Stem Cell Fate The Ras guanine nucleotide exchange factor Sos1 and its adaptor Grb2 are multidomain proteins that couple fibroblast growth factor signaling to activation of the Ras-Erk pathway during mammalian development and drive embryonic stem cells toward the primitive endoderm (PrE) lineage. Researchers showed that the ability of Sos1/Grb2 to appropriately regulate pluripotency and differentiation factors and to initiate PrE development requires collective binding of multiple Sos1/Grb2 domains to their protein and phospholipid ligands. [Cell] Abstract | Graphical Abstract Interplay of LRRK2 with Chaperone-Mediated Autophagy Investigators found leucine-rich repeat kinase 2 (LRRK2) to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. Cells responded to LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell-derived dopaminergic neurons and brains of Parkinson’s disease patients with LRRK2 mutations. [Nat Neurosci] Abstract | Press Release Arf Tumor Suppressor and MicroRNA-205 Regulate Cell Adhesion and Formation of Extraembryonic Endoderm from Pluripotent Stem Cells Although the p19Arf protein is not detected in most tissues of fetal or young adult mice, it is physiologically expressed in the fetal yolk sac, a tissue derived from the extraembryonic endoderm (ExEn). Expression of the mouse p19Arf protein marks late stages of ExEn differentiation in cultured embryoid bodies (EBs) derived from either embryonic stem cells or induced pluripotent stem cells. Arf inactivation delays differentiation of the ExEn lineage within EBs, but not the formation of other germ cell lineages from pluripotent progenitors. [Proc Natl Acad Sci USA] Abstract | Full Article An Ex Vivo Gene Therapy Approach to Treat Muscular Dystrophy Using Inducible Pluripotent Stem Cells Researchers showed the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem cells generated from fibroblasts of mice lacking both dystrophin and utrophin. They corrected the phenotype of dystrophic induced pluripotent stem cells using a Sleeping Beauty transposon system carrying the micro-utrophin gene, differentiated these cells into skeletal muscle progenitors and transplanted them back into dystrophic mice. [Nat Commun] Abstract | Press Release MacroH2A Histone Variants Act as a Barrier Upon Reprogramming towards Pluripotency Using fibroblasts derived from macroH2A double knockout mice, researchers showed that these histone variants act cooperatively as a barrier to induced pluripotency. Through manipulation of macroH2A isoforms, they further demonstrated that macroH2A2 is the predominant barrier to reprogramming. [Nat Commun] Abstract Activation of PDK-1 Maintains Mouse Embryonic Stem Cell Self-Renewal in a PKB-Dependent Manner By using a modified Flp recombinase system, researchers expressed activated alleles of 3-phosphoinositide-dependent protein kinase-1 (PDK-1) and protein kinase B (PKB) to create stable, isogenic embryonic stem cell lines to further study the role of the phosphatidylinositol 3′ kinase signaling pathway in stem cell fate determination. [Oncogene] Full Article Derivation of a Germline Competent Transgenic Fischer 344 Embryonic Stem Cell Line Fischer344 (F344) males carrying an enhanced green fluorescence protein (EGFP) transgene were used as the founder animals for the derivation of embryonic stem (ES) cell lines. One male ES cell line, F344-Tg.EC4011, was further evaluated for germline competence by injection into Dark Agouti X Sprague Dawley (SD) blastocysts. Resulting chimeric animals were bred with wild-type SD mates and germline transmissibility of the ES cell line was confirmed by identification of pups carrying the ES cell line-derived EGFP transgene. [PLoS One] Full Article Lamin A/C Haploinsufficiency Modulates the Differentiation Potential of Mouse Embryonic Stem Cells Researchers investigated the differentiation potential of mouse embryonic stem cells containing reduced levels of lamin A/C by detailed lineage analysis of embryoid bodies derived from these cells by in vitro culture. [PLoS One] Full Article |