Sphingosine-1-phosphate (S1P), an important sphingolipid metabolite, regulates diverse cellular processes, including cell survival, growth, and differentiation. Here we show that S1P signaling is critical for neural and vascular development. Sphingosine kinase-null mice exhibited a deficiency of S1P which severely disturbed neurogenesis, including neural tube closure, and angiogenesis and caused embryonic lethality. A dramatic increase in apoptosis and a decrease in mitosis were seen in the developing nervous system. S1P 1 receptor-null mice also showed severe defects in neurogenesis, indicating that the mechanism by which S1P promotes neurogenesis is, in part, signaling from the S1P 1 receptor. Thus, S1P joins a growing list of signaling molecules, such as vascular endothelial growth factor, which regulate the functionally intertwined pathways of angiogenesis and neurogenesis. Our findings also suggest that exploitation of this potent neuronal survival pathway could lead to the development of novel therapeutic approaches for neurological diseases.Sphingosine-1-phosphate (S1P) is a signaling molecule that is crucial for the regulation of several diverse cellular events, including cell survival, growth, differentiation, motility, and calcium mobilization (29). Recently, numerous studies on S1P have demonstrated its importance in the development of the vascular system (1,14,16,18), the heart (15), and immunity (2, 5, 21) by signaling through a family of G protein-coupled receptors designated S1P 1 to S1P 5 . The S1P signaling pathway through S1P receptors induces activation of the protein kinase Akt, phosphatidylinositol 3-kinase, the small GTPase Rac, phospholipase C, and extracellular signal-regulated kinase, leading to cell survival and proliferation (11). In higher plants, S1P also plays an important role in calcium regulation and the control of guard cells (7).Sphingosine kinase (SphK) is an enzyme that catalyzes the phosphorylation of sphingosine to form S1P. Two isoforms of mammalian SphK (SphK1 and SphK2) have been cloned and characterized (13,17). Recent studies revealed that overexpression of SphK2 suppressed cell growth and also markedly enhanced apoptosis in cultured cells (12,19), in sharp contrast to findings for SphK1, which generally promoted cell survival and growth (26,27).Recently, we generated SphK1 knockout mice to study the enzyme's physiological functions (3). The SphK1 Ϫ/Ϫ mice were viable and fertile and lacked any obvious abnormalities, although total SphK activity was substantially, but not completely, reduced. These results raise the possibility that SphK1 and SphK2 might have redundant functions in mice and that SphK2 could compensate for a deficiency in SphK1 activity. To investigate the physiological functions of both isoforms, we generated SphK2 knockout mice, as well as SphK1/SphK2 double-knockout mice. Simultaneous deletion of both enzymes resulted in mice with undetectable levels of S1P. The studies on S1P-deficient mice described herein reveal a novel function for S1P signaling ...
In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.
Until recently, Histoplasma capsulatum was believed to harbour three varieties, var. capsulatum (chiefly a New World human pathogen), var. duboisii (an African human pathogen) and var. farciminosum (an Old World horse pathogen), which varied in clinical manifestations and geographical distribution. We analysed the phylogenetic relationships of 137 individuals representing the three varieties from six continents using DNA sequence variation in four independent protein-coding genes. At least eight clades were idengified: (i) North American class 1 clade; (ii) North American class 2 clade; (iii) Latin American group A clade; (iv) Latin American group B clade; (v) Australian clade; (vi) Netherlands (Indonesian?) clade; (vii) Eurasian clade and (viii) African clade. Seven of eight clades represented genetically isolated groups that may be recognized as phylogenetic species. The sole exception was the Eurasian clade which originated from within the Latin American group A clade. The phylogenetic relationships among the clades made a star phylogeny. Histoplasma capsulatum var. capsulatum individuals were found in all eight clades. The African clade included all of the H. capsulatum var. duboisii individuals as well as individuals of the other two varieties. The 13 individuals of var. farciminosum were distributed among three phylogenetic species. These findings suggest that the three varieties of Histoplasma are phylogenetically meaningless. Instead we have to recognize the existence of genetically distinct geographical populations or phylogenetic species. Combining DNA substitution rates of protein-coding genes with the phylogeny suggests that the radiation of Histoplasma started between 3 and 13 million years ago in Latin America.
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