Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Many components and pathways transducing multifaceted and deleterious effects of stress stimuli remain ill-defined. The Ran-binding protein 2 (RanBP2) interactome modulates the expression of a range of clinical and cell-context-dependent manifestations upon a variety of stressors. We examined the role of Ranbp2 haploinsufficiency on cellular and metabolic manifestations linked to tyrosine-hydroxylase (TH(+)) dopaminergic neurons and glial cells of the brain and retina upon acute challenge to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonian neurotoxin, which models facets of Parkinson disease. MPTP led to stronger akinetic parkinsonism and slower recovery in Ranbp2 (+/-) than wild-type mice without viability changes of brain TH(+)-neurons of either genotype, with the exception of transient nuclear atypia via changes in chromatin condensation of Ranbp2 (+/-) TH(+)-neurons. Conversely, the number of wild-type retinal TH(+)-amacrine neurons compared to Ranbp2 (+/-) underwent milder declines without apoptosis followed by stronger recoveries without neurogenesis. These phenotypes were accompanied by a stronger rise of EdU(+)-proliferative cells and non-proliferative gliosis of GFAP(+)-Müller cells in wild-type than Ranbp2 (+/-) that outlasted the MPTP-insult. Finally, MPTP-treated wild-type and Ranbp2 (+/-) mice present distinct metabolic footprints in the brain or selective regions thereof, such as striatum, that are supportive of RanBP2-mediated regulation of interdependent metabolic pathways of lysine, cholesterol, free-fatty acids, or their β-oxidation. These studies demonstrate contrasting gene-environment phenodeviances and roles of Ranbp2 between dopaminergic and glial cells of the brain and retina upon oxidative stress-elicited signaling and factors triggering a continuum of metabolic and cellular manifestations and proxies linked to oxidative stress, and chorioretinal and neurological disorders such as Parkinson.     

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.     

Depigmentation and coat colour variegation in mice treated with 8-hydroxyquinoline

Zusammenfassung Die Melanogenese wird bei Mäusen durch 8-Hydroxychinolin selektiv gehemmt. Besonders bei behandelten weiblichen Tieren des Stammes C57BL entwickelt sich ein aussergewöhnliches Haarmuster mit abwechselnden schwarzen und weissen Streifen oder Kreisen. Diese reversible Wirkung wurde bei neugeborenen Mäusen oder nach Behandlung mit Cu-reaktiven Substanzen nicht beobachtet.

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I wish to thank Professor D. G.Harnden and Dr.Mary Lyon for their interest and advice, and Mr. C. R.Richardson for technical assistance. The work was supported by the Birmingham Branch of the British Empire Cancer Campaign for Research.     

Induction of brain tumours in high yield by administration of N-ethyl-N-nitrosourea to newborn rats

Zusammenfassung Durch einmalige Verabreichung von 10 mg/kg N-Äthyl-N-Nitrosoharnstoff am 1. Tag nach der Geburt wurden bei 33/34 Ratten 53 Hirntumoren, 9 Tumoren des Rückenmarkes, aber nur 9 im peripheren Nervensystem erzeugt, was eine bedeutend gesteigerte Rate von Hirntumoren bedeutet.

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We thank MissMary Trumper and MissValerie Nash for technical assistance and the Cancer Research Campaign for financial support of C.E.S.