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The neural fate is generally considered to be the intrinsic direction of embryonic stem (ES) cell differentiation. However, little is known about the intracellular mechanism that leads undifferentiated cells to adopt the neural fate in the absence of extrinsic inductive signals. Here we show that the zinc-finger nuclear protein Zfp521 is essential and sufficient for driving the intrinsic neural differentiation of mouse ES cells. In the absence of the neural differentiation inhibitor BMP4, strong Zfp521 expression is intrinsically induced in differentiating ES cells. Forced expression of Zfp521 enables the neural conversion of ES cells even in the presence of BMP4. Conversely, in differentiation culture, Zfp521-depleted ES cells do not undergo neural conversion but tend to halt at the epiblast state. Zfp521 directly activates early neural genes by working with the co-activator p300. Thus, the transition of ES cell differentiation from the epiblast state into neuroectodermal progenitors specifically depends on the cell-intrinsic expression and activator function of Zfp521., Previous studies, particularly in amphibians, have demonstrated that the initial step of vertebrate neural differentiation from uncommitted embryonic ectodermal cells occurs via a cell-intrinsic mechanism and requires only that inhibitory [...]

Blood lines How the blood system forms during embryonic development is a topic of intensive research, in part because of the potential importance of the process for regenerative medicine. Two main theories have emerged to explain the formation of the haematopoietic stem cells that eventually populate the adult born marrow. One idea is that the haematopoietic stem cell and the endothelial lineage arise independently from the mesoderm; the other is that some haematopoietic and endothelial lineages derive from a specialized progenitor called a haemangioblast. Three papers in this issue unify the two theories. Both are correct: the haemangioblast does generate haematopoietic cells, but via a haemogenic endothelium intermediate. Recent studies have indicated that embryonic blood is produced by endothelial cells, which also form blood vessels and arteries. This paper uses a direct imaging and cell tracking approach to directly show that embryonic endothelial cells do produce blood. By imaging cells over days, they were able to show that a subset of embryonic endothelial cells formed blood cells. Despite decades of research, the identity of the cells generating the first haematopoietic cells in mammalian embryos is unknown.sup.1. Indeed, whether blood cells arise from mesodermal cells, mesenchymal progenitors, bipotent endothelial-haematopoietic precursors or haemogenic endothelial cells remains controversial.sup.2,3,4,5,6,7,8,9. Proximity of endothelial and blood cells at sites of embryonic haematopoiesis, as well as their similar gene expression, led to the hypothesis of the endothelium generating blood. However, owing to lacking technology.sup.10 it has been impossible to observe blood cell emergence continuously at the single-cell level, and the postulated existence of haemogenic endothelial cells remains disputed.sup.1. Here, using new imaging and cell-tracking methods, we show that embryonic endothelial cells can be haemogenic. By continuous long-term single-cell observation of mouse mesodermal cells generating endothelial cell and blood colonies, it was possible to detect haemogenic endothelial cells giving rise to blood cells. Living endothelial and haematopoietic cells were identified by simultaneous detection of morphology and multiple molecular and functional markers. Detachment of nascent blood cells from endothelium is not directly linked to asymmetric cell division, and haemogenic endothelial cells are specified from cells already expressing endothelial markers. These results improve our understanding of the developmental origin of mammalian blood and the potential generation of haematopoietic stem cells from embryonic stem cells., Author(s): Hanna M. Eilken [sup.1] , Shin-Ichi Nishikawa [sup.2] , Timm Schroeder [sup.1] Author Affiliations: (1) Institute of Stem Cell Research, Helmholtz Center Munich--German Research Center for Environmental Health (GmbH), [...]

Author(s): Daisuke Yamazaki [1, 2]; Shiro Suetsugu [1, 2]; Hiroaki Miki [3, 4]; Yuki Kataoka [5]; Shin-Ichi Nishikawa [6]; Takashi Fujiwara [7]; Nobuaki Yoshida [5]; Tadaomi Takenawa (corresponding author) [1, [...]

Author(s): Emi K. Nishimura [1, 2, 3]; Siobhán A. Jordan [4]; Hideo Oshima [3, 5]; Hisahiro Yoshida [1]; Masatake Osawa [6]; Mariko Moriyama [6]; Ian J. Jackson [4]; Yann Barrandon [...]

Author(s): Jun Yamashita (corresponding author) [1]; Hiroshi Itoh [1]; Masanori Hirashima [2]; Minetaro Ogawa [2]; Satomi Nishikawa [2]; Takami Yurugi [1]; Makoto Naito [3]; Kazuwa Nakao [1]; Shin-Ichi Nishikawa [2] [...]

Transcription factors with basic helix-loop-helix (HLF) motifs are essential for certain cell differentiation processes during multicellular organism development. The functions of the transcription factors are inhibited by Id proteins, by suppression of their heterodimerization partners vial the HLH domains. Id2 is found to be essential for normal development of mice, and is require for the generation of peripheral lymphoid organs and NK cells.

Mice lacking CXCR4, the cell surface receptor, were generated to elucidate the physiological functions of CXCR4. The functions of CXCR4 during embryogenesis were studied by developing embryos by in situ hybridization. CXCR4 and PBSF/SDF-1 were found to be responsible for the formation of a mature vascular system, supplying the gastrointestinal tract. The results suggested that CXCR4 is a main physiological receptor for PBSF/SDF-1.

Pre-B-cell-growth-stimulating factor/stromal cell-derived factor-1 (PBSF/SDF-1), a member of the CXC group of chemokines, has an important physiological role in development. Mutant mice with disrupted gene encoding PBSF/SDF-1 die perinatally. The mutant embryos have reduced B-cell progenitors in both fetal liver and bone marrow, while they have reduced myeloid progenitors only in the bone marrow. This indicates that PBSF/SDF-1 regulates B-cell lymphopoiesis and bone-marrow myelopoiesis. The mutants also have a cardiac ventricular septal defect.