Peutz-Jeghers syndrome (PJS) is a dominantly inherited human disorder characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. LKB1 (STK11) serine͞threonine kinase is the product of the causative gene of PJS, which has been mapped to chromosome 19p13.3. However, several studies have produced results that are not consistent with a link between LKB1 gene mutation and PJS. We constructed a knockout gene mutation of Lkb1 to determine whether it is the causative gene of PJS and to examine the biological role of the Lkb1 gene. Lkb1 ؊/؊ mice died in utero between 8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, Lkb1 ؊/؊ embryos were generally smaller than their age-matched littermates, showed developmental retardation, and did not undergo embryonic turning. Multiple gastric adenomatous polyps were observed in 10-to 14-month-old Lkb1 ؉/؊ mice. Our results indicate that functional Lkb1 is required for normal embryogenesis and that it is related to tumor development. The Lkb1 ؉/؊ mouse is suitable for studying molecular mechanism underlying the development of inherited gastric tumors in PJS.tumor ͉ embryo development

Nakao K. Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. Am J Physiol Endocrinol Metab 297: E1339 -E1348, 2009. First published October 6, 2009 doi:10.1152/ajpendo.00272.2009.-Ctype natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia. blood level elevation THE SKELETON OF A VERTEBRATE is formed by two different processes of ossification, membranous and endochondral. Most of the craniofacial bones are developed through membranous ossification (desmocranium). On the other hand, endochondral ossification leads to the development of vertebrae, long bones, and base of skull (chondrocranium) by the sequential formation and degradation of cartilaginous structure growth plates. It has been reported that many factors are implicated in the regulation of endochondral ossification, and mutations of these factors often cause skeletal dysplasias (10,18,35).

Calponin from chicken gizzard induced polymerization of actin in the presence of 10 mM KCl. Only 2 min after the addition of KCl in the presence of a 0.0625-0.25:1 molar ratio of calponin to actin, a Poisson-type length distribution (with an average length of approx. 0.7 micron) was observed with formed actin filaments. This result suggests that calponin-actin complexes served as nuclei for rapid elongation. Calponin caused a rapid polymerization of actin even in G-buffer (2 mM Tris/HCl, pH 8.0) which is usually used for depolymerization of actin filaments. Binding of calponin at a level of up to 1.25 mol per mol of actin was observed in the actin filaments formed in the presence of calponin at very low ionic strengths. When actin filaments were exposed to 3.3 mM KCl, by dilution with G-buffer, a rapid depolymerization occurred. Addition of calponin greatly retarded the depolymerization process and, in the presence of an equimolar ratio of calponin to actin, depolymerization hardly occurred. In the presence of calmodulin, this inhibitory effect on depolymerization was reversed by Ca2+, releasing calponin from actin filaments.

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BackgroundGas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN).MethodsThe aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes.ResultsIn 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation.ConclusionsGas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.