Human neural progenitors express functional lysophospholipid receptors that regulate cell growth and morphology

<p>Abstract</p> <p>Background</p> <p>Lysophospholipids regulate the morphology and growth of neurons, neural cell lines, and neural progenitors. A stable human neural progenitor cell line is not currently available in which to study the role of lysophospholipids in human neural development. We recently established a stable, adherent human embryonic stem cell-derived neuroepithelial (hES-NEP) cell line which recapitulates morphological and phenotypic features of neural progenitor cells isolated from fetal tissue. The goal of this study was to determine if hES-NEP cells express functional lysophospholipid receptors, and if activation of these receptors mediates cellular responses critical for neural development.</p> <p>Results</p> <p>Our results demonstrate that Lysophosphatidic Acid (LPA) and Sphingosine-1-phosphate (S1P) receptors are functionally expressed in hES-NEP cells and are coupled to multiple cellular signaling pathways. We have shown that transcript levels for S1P1 receptor increased significantly in the transition from embryonic stem cell to hES-NEP. hES-NEP cells express LPA and S1P receptors coupled to G_i/oG-proteins that inhibit adenylyl cyclase and to G_q-like phospholipase C activity. LPA and S1P also induce p44/42 ERK MAP kinase phosphorylation in these cells and stimulate cell proliferation via G_i/ocoupled receptors in an Epidermal Growth Factor Receptor (EGFR)- and ERK-dependent pathway. In contrast, LPA and S1P stimulate transient cell rounding and aggregation that is independent of EGFR and ERK, but dependent on the Rho effector p160 ROCK.</p> <p>Conclusion</p> <p>Thus, lysophospholipids regulate neural progenitor growth and morphology through distinct mechanisms. These findings establish human ES cell-derived NEP cells as a model system for studying the role of lysophospholipids in neural progenitors.</p

Identification of Quantitative Trait Loci for Susceptibility to Mouse Adenovirus Type 1

Adult SJL/J mice are highly susceptible to mouse adenovirus type 1 (MAV-1) infections, whereas other inbred strains, including BALB/cJ, are resistant (K. R. Spindler, L. Fang, M. L. Moore, C. C. Brown, G. N. Hirsch, and A. K. Kajon, J. Virol. 75:12039-12046, 2001). Using congenic mouse strains, we showed that the H-2(s) haplotype of SJL/J mice is not associated with susceptibility to MAV-1. Susceptibility of MAV-1-infected (BALB/cJ × SJL/J)F(1) mice was intermediate between that of SJL/J mice and that of BALB/cJ mice, indicating that susceptibility is a genetically controlled quantitative trait. We mapped genetic loci involved in mouse susceptibility to MAV-1 by analysis of 192 backcross progeny in a genome scan with 65 simple sequence length polymorphic markers. A major quantitative trait locus (QTL) was detected on chromosome 15 (Chr 15) with a highly significant logarithm of odds score of 21. The locus on Chr 15 alone accounts for 40% of the total trait variance between susceptible and resistant strains. QTL modeling of the data indicated that there are a number of other QTLs with small effects that together with the major QTL on Chr 15 account for 54% of the trait variance. Identification of the major QTL is the first step in characterizing host genes involved in susceptibility to MAV-1

Association of RON tyrosine kinase with the Jaagsiekte sheep retrovirus envelope glycoprotein

AbstractThe envelope (Env) of Jaagsiekte sheep retrovirus (JSRV) functions as an oncoprotein. One of the mechanisms of JSRV-induced cell transformation that has been proposed for epithelial cells involves JSRV Env binding Hyaluronidase 2 (the JSRV receptor), thereby inducing its degradation and allowing the release and activation of RON tyrosine kinase which is normally suppressed by HYAL-2. In this study, we report that HYAL-2 and RON are not critical for the JSRV Env-induced transformation of the rat epithelial cell line IEC-18, while the cytoplasmic tail of the JSRV Env is critical to transform this cell line. We have also determined that RON can associate with the JSRV Env under normal and stringent conditions. In addition, the cytoplasmic tail of the JSRV and the enJS5F16 (non oncogenic JSRV-related endogenous retrovirus) Env proteins appears to have a major influence on the activation status of RON. Thus, it appears that the interaction of the JSRV Env with RON is more complex than previously thought and requires further investigation