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The family of interferon-induced transmembrane protein (Ifitm/mil/fragilis) genes encodes cell surface proteins that may modulate cell adhesion and influence cell differentiation. Mouse Ifitm1 and -3, which are expressed in primordial germ cells (PGCs), are implicated to have roles in germ cell development, but the specific functions have been unclear. Our results show that Ifitm1 activity is required for PGC transit from the mesoderm into the endoderm, and that it appears to act via a repulsive mechanism, such that PGCs avoid Ifitm1-expressing tissues. In contrast, Ifitm3, which is expressed in migratory PGCs, is sufficient to confer autonomous PGC-like homing properties to somatic cells. These guidance activities are mediated by the N-terminal extracellular domain of the specific IFITM, which cannot be substituted by that of another family member. Complex homo- and/or heterotypic intercellular interactions among various IFITMs in PGCs and neighboring cells may underpin coordinated germ cell guidance in mice.

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The transcriptional activator Gcn4p is considered the master regulator of amino acid metabolism in Saccharomyces cerevisiae and is required for the transcriptional response to amino acid starvation. Here it is shown that Gcn4p plays a previously undescribed role in regulating adaptation to anaerobic growth. A gcn4 mutant exhibited a highly extended lag phase after a shift to anaerobiosis that was the result of L-serine depletion. In addition, the one-carbon metabolism and purine biosynthesis transcriptional regulator Bas1p were strictly required for anaerobic growth on minimal medium, and this was similarly due to L-serine limitation in bas1 mutants. The induction of one-carbon metabolism during anaerobiosis is needed to increase the supply of L-serine from the glycine and threonine pathways. Using a number of experimental approaches, we demonstrate that these transcription regulators play vital roles in regulating L-serine biosynthesis in the face of increased demand during adaptation to anaerobiosis. This increased L-serine requirement is most likely due to anaerobic remodeling of the cell wall, involving de novo synthesis of a large number of very serine-rich mannoproteins and an increase in the total serine content of the cell wall. During anaerobic starvation for L-serine, this essential amino acid is preferentially directed to the cell wall, indicating the existence of a regulatory mechanism to balance competing cellular demands.Saccharomyces cerevisiae can grow rapidly aerobically and anaerobically, and this has led to its use in the study of oxygen sensing and the requirement of molecular oxygen for metabolism. Under anaerobic conditions cells cannot synthesize sterols and unsaturated fatty acids because the two pathways require molecular oxygen (1). Several studies have identified the genome-wide transcriptional responses of yeast growing in aerobic or anaerobic conditions (2-6), however, many environments are subject to dynamic fluctuations in oxygen tension and, hence, there is current interest in how organisms respond to changes in oxygen level (3,7,8). Under anaerobic conditions proteins involved in amino acid metabolism are synthesized at higher levels (9). We have previously reported that cells lacking the Gcn4p transcription factor regulating genes involved in amino acid metabolism have a growth defect under anaerobic conditions. This indicates that there may be an altered requirement for some Gcn4p-dependent aspect of amino acid biosynthesis in anaerobic cells compared with aerobic (10).In S. cerevisiae and related fungi, including Candida albicans, Gcn4p is a master transcriptional activator that directly activates over 30 amino acid biosynthetic genes for biosynthesis of 19 amino acids, as well as regulating many other cellular processes, including purine biosynthesis, organelle biosynthesis, autophagy, glycogen homeostasis, and stress responses (11). The mechanisms involved in Gcn4p regulation have been reviewed by Hinnebusch (12). When cells are subjected to stresses such as amino acid, puri...