Development of dopaminergic neurons in the mammalian brain

Dopaminergic neurons in the mammalian brain have received substantial attention in the past given their fundamental role in several body functions and behaviours. The largest dopaminergic population is found in two nuclei of the ventral midbrain. Cells of the substantia nigra pars compacta are involved in the control of voluntary movements and postural reflexes, and their degeneration in the adult brain leads to Parkinson’s disease. Cells of the ventral tegmental area modulate rewarding and cognitive behaviours, and their dysfunction is involved in the pathogenesis of addictive disorders and schizophrenia. Because of their clinical relevance, the embryonic development and maintenance of the midbrain dopaminergic cell groups in the adult have been intensively studied in recent years. In the present review, we provide an overview of the mechanisms and factors involved in the development of dopaminergic neurons in the mammalian brain, with a special emphasis on the midbrain dopaminergic population. Received 17 August 2005; received after revision 28 September 2005; accepted 21 October 2005     

Effect of phytic acid on diamine oxidase activity in germinating pea seeds.

Diamine oxidase present in the cotyledons of germinating pea seeds is induced by phytic acid but the embryo enzyme is not affected. Polyamines have no effect on phytase activity of the cotyledon or embryo.     

The rapid drift of the Indian tectonic plate

The breakup of the supercontinent Gondwanaland into Africa, Antarctica, Australia and India about 140 million years ago, and consequently the opening of the Indian Ocean, is thought to have been caused by heating of the lithosphere from below by a large plume whose relicts are now the Marion, Kerguelen and Réunion plumes. Plate reconstructions based on palaeomagnetic data suggest that the Indian plate attained a very high speed (18-20 cm yr(-1) during the late Cretaceous period) subsequent to its breakup from Gondwanaland, and then slowed to approximately 5 cm yr(-1) after the continental collision with Asia approximately 50 Myr ago. The Australian and African plates moved comparatively less distance and at much lower speeds of 2-4 cm yr(-1) (refs 3-5). Antarctica remained almost stationary. This mobility makes India unique among the fragments of Gondwanaland. Here we propose that when the fragments of Gondwanaland were separated by the plume, the penetration of their lithospheric roots into the asthenosphere were important in determining their speed. We estimated the thickness of the lithospheric plates of the different fragments of Gondwanaland around the Indian Ocean by using the shear-wave receiver function technique. We found that the fragment of Gondwanaland with clearly the thinnest lithosphere is India. The lithospheric roots in South Africa, Australia and Antarctica are between 180 and 300 km deep, whereas the Indian lithosphere extends only about 100 km deep. We infer that the plume that partitioned Gondwanaland may have also melted the lower half of the Indian lithosphere, thus permitting faster motion due to ridge push or slab pull.     

Effect of lindane on the skin of albino rats

Zusammenfassung Langfristig wiederholte Lindan-Applikation ruft bei der Abinoratte histopathologische hautveränderungen hervor: Hyperkeratinisation, intraepidermale und dermale Abszesse, Infiltration polymorphkerniger Zellen sowie Vakuolisation und Vielkernigkeit in der Malpighi-Schicht.

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Pury -isomer of 1,2,3,4,5,6-hexachlorocyclohexane.     

Naturally occurring pea diamine oxidase inhibitors obtained fromSorghum vulgare during germination

Summary During germination ofSorghum vulgare seeds, inhibitors of pea diamine oxidase appeared in the embryos. One was heat labile, dialysable and inhibited the enzyme in vitro, while another was heat stable and inhibited the enzyme synthesis when pea seeds were soaked and allowed to germinate in the extract containing the inhibitors.Acknowledgments. We thank Dr S.K. Srivastava for his helpful suggestions and access to his facilities.     

Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

The large conductance calcium-sensitive potassium (BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the alpha subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca(2+) sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.     

Genotype-based screen for ENU-induced mutations in mouse embryonic stem cells

The ability to generate mutations is a prerequisite to functional genetic analysis. Despite a long history of using mice as a model system for genetic analysis, the scientific community has not generated a comprehensive collection of multiple alleles for most mouse genes. The chemical mutagen of choice for mouse has been N-ethyl-N-nitrosourea (ENU), an alkylating agent that mainly causes base substitutions in DNA, and therefore allows for recovery of complete and partial loss-, as well as gain-, of-function alleles . Specific locus tests designed to detect recessive mutations showed that ENU is the most efficient mutagen in mouse with an approximate mutation rate of 1 in 1,000 gametes. In fact, several genome-wide and region-specific screens based on phenotypes have been carried out. The anticipation of the completion of the human and mouse genome projects, however, now emphasizes genotype-driven genetics--from sequence to mutants. To take advantage of the mutagenicity of ENU and its ability to create allelic series of mutations, we have developed a complementary approach to generating mutations using mouse embryonic stem (ES) cells. We show that a high mutation frequency can be achieved and that modulating DNA-repair activities can enhance this frequency. The treated cells retain germline competency, thereby rendering this approach applicable for efficient generation of an allelic series of mutations pivotal to a fine-tuned dissection of biological pathways.     

Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions

DNA lesions can often block DNA replication, so cells possess specialized low-fidelity, and often error-prone, DNA polymerases that can bypass such lesions and promote replication of damaged DNA. The Saccharomyces cerevisiae RAD30 and human hRAD30A encode Pol eta, which bypasses a cis-syn thymine-thymine dimer efficiently and accurately. Here we show that a related human gene, hRAD30B, encodes the DNA polymerase Pol iota, which misincorporates deoxynucleotides at a high rate. To bypass damage, Pol iota specifically incorporates deoxynucleotides opposite highly distorting or non-instructional DNA lesions. This action is combined with that of DNA polymerase Pol zeta, which is essential for damage-induced mutagenesis, to complete the lesion bypass. Pol zeta is very inefficient in inserting deoxynucleotides opposite DNA lesions, but readily extends from such deoxynucleotides once they have been inserted. Thus, in a new model for mutagenic bypass of DNA lesions in eukaryotes, the two DNA polymerases act sequentially: Pol iota incorporates deoxynucleotides opposite DNA lesions, and Pol zeta functions as a mispair extender.     

Impaired Rho GTPase activation abrogates cell polarization and migration in macrophages with defective lipolysis

Infiltration of monocytes and macrophages into the site of inflammation is critical in the progression of inflammatory diseases such as atherosclerosis. Cell migration is dependent on the continuous organization of the actin cytoskeleton, which is regulated by members of the small Rho GTPase family (RhoA, Cdc42, Rac) that are also important for the regulation of signal transduction pathways. We have recently reported on reduced plaque formation in an atherosclerotic mouse model transplanted with bone marrow from adipose triglyceride lipase-deficient (Atgl-/-) mice. Here we provide evidence that defective lipolysis in macrophages lacking ATGL, the major enzyme responsible for triacylglycerol hydrolysis, favors an anti-inflammatory M2-like macrophage phenotype. Our data implicate an as yet unrecognized principle that insufficient lipolysis influences macrophage polarization and actin polymerization, resulting in impaired macrophage migration. Sustained phosphorylation of focal adhesion kinase [due to inactivation of its phosphatase by elevated levels of reactive oxygen species (ROS)] results in defective Cdc42, Rac1 and RhoA activation and in increased and sustained activation of Rac2. Inhibition of ROS production restores the migratory capacity of Atgl-/- macrophages. Since monocyte and macrophage migration are a prerequisite for infiltrating the arterial wall, our results provide a molecular link between lipolysis and the development of atherosclerosis.