A wealth of indirect data suggest that the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate (S1P) receptor plays important roles in development. In vitro, it activates several forms of development-related signal transduction and regulates cellular proliferation, differentiation and survival. It is expressed during embryogenesis, and mutation of an H218-like gene in zebrafish leads to profound defects in embryonic development. Nevertheless, the in vivo functions served by H218 signalling have not been directly investigated. We report here that mice in which the H218 gene has been disrupted are unexpectedly born with no apparent anatomical or physiological defects. In addition, no abnormalities were observed in general neurological development, peripheral axon growth or brain structure. However, between 3 and 7 weeks of age, H218(-/-) mice have seizures which are spontaneous, sporadic and occasionally lethal. Electroencephalographic abnormalities were identified both during and between the seizures. At a cellular level, whole-cell patch-clamp recordings revealed that the loss of H218 leads to a large increase in the excitability of neocortical pyramidal neurons. Therefore, H218 plays an essential, unanticipated and functionally important role in the proper development and/or mediation of neuronal excitability.

Ciliary neurotrophic factor receptor (Y (CNTFRo() is essential for normal embryonic development and may be involved in postnatal and adult neuronal maintenance. In addition, a rapidly growing body of evidence suggests that CNTFRo(serves as a site of action for future growth factor therapeutics capable of treating a wide variety of disorders resulting from neuronal loss. We raised two polyclonal, anti-CNTFRoc antisera against synthetic peptides corresponding to independent regions of rat CNTFRo(. Western blot and immunohistochemical analyses indicated that affinity-purified preparations of both antisera specifically recognize CNTFRa. In the adult brain, the highest levels of CNTFRcv immunoreactivity were found in the perikarya, dendrites and, occasionally, the axons of several distinct classes of neurons including hippocampal formation neurons, some sensory neurons, and many neurons involved in motor control. CNTFRo(immunoreactivity also was concentrated in the following: perikarya, dendrites, and axons of ventral horn motor neurons in adult spinal cord; perikarya and axons of adult dorsal root ganglion neurons; and axons in adult peripheral nerve. In embryonic tissue, the highest levels of CNTFRcv immunoreactivity were observed in differentiating neurons and their processes. Therefore, the present data suggest that CNTFRcv serves several diverse functions in adulthood and during development.

S1P 2 sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology, and migration in many cell types in vitro. Here, we report that S1P 2 −/− mice develop clonal B-cell lymphomas with age, such that approximately half of the animals display this neoplasm by 1.5 to 2 years of age. Histologic, immunophenotypic, and molecular analyses revealed a uniform tumor phenotype with features of germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL). Tumor formation was preceded by increases in GC B cells and CD69 + T cells, as well as an increased formation of spontaneous GCs, suggesting that S1P 2 loss may promote lymphomagenesis in part by disrupting GC B-cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P 2 gene disruption is remarkably restricted to DLBCL. In humans, 28 of 106 (26%) DLBCL samples were found to harbor multiple somatic mutations in the 5′ sequences of the S1P 2 gene. Mutations displayed features resembling those generated by the IgV-associated somatic hypermutation mechanism, but were not detected at significant levels in normal GC B cells, indicating a tumor-associated aberrant function. Collectively, our data suggest that S1P 2 signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P 2 −/− mice, its onset at old age, and the relative lack of other neoplasms identify these mice as a novel, and potentially valuable, model for this highly prevalent and aggressive human malignancy. [Cancer Res 2009;69(22):8686-92]