Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development.

The ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors. ErbB2(-/-) mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR and postsynaptic expression of the genes encoding the alpha-AChR, AChE, epsilon-AChR, and the RI subunit of the cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and reveal different survival requirements for distinct motoneuron populations.

The role of SF/HGF and c-Met in the development of skeletal muscle.

Hypaxial skeletal muscles develop from migratory and non-migratory precursor cells that are generated by the lateral lip of the dermomyotome. Previous work shows that the formation of migratory precursors requires the c-Met and SF/HGF genes. We show here that in mice lacking c-Met or SF/HGF, the initial development of the dermomyotome proceeds appropriately and growth and survival of cells in the dermomyotome are not affected. Migratory precursors are also correctly specified, as monitored by the expression of Lbx1. However, these cells remain aggregated and fail to take up long range migration. We conclude that parallel but independent cues converge on the migratory hypaxial precursors in the dermomyotomal lip after they are laid down: a signal given by SF/HGF that controls the emigration of the precursors, and an as yet unidentified signal that controls Lbx1. SF/HGF and c-Met act in a paracrine manner to control emigration, and migratory cells only dissociate from somites located close to SF/HGF-expressing cells. During long range migration, prolonged receptor-ligand-interaction appears to be required, as SF/HGF is expressed both along the routes and at the target sites of migratory myogenic progenitors. Mice that lack c-Met die during the second part of gestation due to a placental defect. Rescue of the placental defect by aggregation of tetraploid (wild type) and diploid (c-Met-/-) morulae allows development of c-Met mutant animals to term. They lack muscle groups that derive from migratory precursor cells, but display otherwise normal skeletal musculature.

[Nitric oxide, L-arginine and the kidney. Experimental studies of new therapy approaches]. / Stickstoffmonoxid, L-Arginin und die Niere. Experimentelle Studien zu neuen Therapieansätzen.

BACKGROUND: Nitric oxide (NO) is a small gaseous molecule with multiple biological effects. NO is produced from the semi-essential amino acid L-arginine by NO synthases (NOS). In the kidney, neuronal NOS (bNOS), which is localized in the macula densa, and endothelial NOS (ecNOS) are involved in the regulation of glomerular hemodynamics. Dysfunction of these enzymes may cause glomerular hypertension and increased intraglomerular platelet aggregation. NO production in high tissue concentrations can be achieved by activation of an inducible NOS isoform (iNOS) and may act as a potent mediator of inflammation in immune-mediated renal diseases. Selective inhibition of iNOS may, therefore, become a novel anti-inflammatory approach in the treatment of glomerulonephritis. Based on experimental data, the potential importance of NO and other metabolites of L-arginine in the pathophysiology and therapy of renal diseases is summarized in this article. CONCLUSION: Modulation of the renal L-arginine/NO-system represents a promising therapeutic target in the treatment of acute an chronic kidney diseases.

Influence of dopaminergic agonists/antagonists on fucose metabolism in the rat brain.

UNLABELLED: Valid indications of a key role for dopaminergic drugs in glycoprotein fucosylation in neuronal tissue in vitro led us to investigate whether the administration of dopaminergic agonists/antagonists influences fucose metabolism in the rat brain in vivo. Three test groups were set up. Group 1 was given L-DOPA (210 mg/l), Group 2 haloperidol (10.5 mg/l) in drinking water, Group 3 served as control. The rats were sacrificed after 8 weeks and enzyme activities in 5 different brain areas were determined concerning the enzymes of the anabolic fucose metabolism: fucokinase, fucose-1-phosphate pyrophosphorylase and fucosyltransferase 1 and 2. Only the specific activity of fucokinase was affected by haloperidol or L-DOPA administration. In the olfactory bulbus, thalamus and cortex, haloperidol decreased fucokinase activity by 21%, 37%, and 39%, respectively (p < 0.05 in each case). No changes were observed in the cerebellum and striatum. Surprisingly, fucokinase activity in the cortex was decreased by L-DOPA (31%, p < 0.05). CONCLUSIONS: Cerebral fucokinase activity is influenced in vivo by dopaminergic drugs in well circumscribed brain areas. Other enzymes of the anabolic fucose metabolism showed no change in activity. It is, therefore, conceivable that these drugs, apart from known mechanisms, exert part of their pharmacological action via a modulation of fucose metabolism.