Although brain-derived neurotrophic factor (BDNF) is linked with an increasing number of conditions causing brain dysfunction, its rolein the postnatal CNS has remained difficult to assess. This is because the bdnf-null mutation causes the death of the animals before BDNF levels have reached adult levels. In addition, the anterograde axonal transport of BDNF complicates the interpretation of area-specific gene deletion. The present study describes the generation of a new conditional mouse mutant essentially lacking BDNF throughout the CNS. It shows that BDNF is not essential for prolonged postnatal survival, but that the behavior of such mutant animals is markedly altered. It also reveals that BDNF is not a major survival factor for most CNS neurons and for myelination of their axons. However, it is required for the postnatal growth of the striatum, and single-cell analyses revealed a marked decreased in dendritic complexity and spine density. In contrast, BDNF is dispensable for the growth of the hippocampus and only minimal changes were observed in the dendrites of CA1 pyramidal neurons in mutant animals. Spine density remained unchanged, whereas the proportion of the mushroom-type spine was moderately decreased. In line with these in vivo observations, we found that BDNF markedly promotes the growth of cultured striatal neurons and of their dendrites, but not of those of hippocampal neurons, suggesting that the differential responsiveness to BDNF is part of a neuron-intrinsic program.

Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily.Michael Becker-André , Irmgard Wiesenberg, Nicole Schaeren-Wiemers, Elisabeth André , Martin Missbach, Jean-Hilaire Saurat, and Carsten Carlberg Correction submitted by Drs. Becker-André , SchaerenWiemers, and André:The article reported the identification of the pineal gland hormone melatonin as a natural ligand of the nuclear orphan receptor RZR␤. The article described transient transfection assays showing stimulation of RZR␤ transactivation by melatonin and in vitro binding studies showing a direct interaction between RZR␤ and melatonin. We were, however, not able to reproduce any of these experiments nor could we determine the reason for this failure. As the central finding of the article is based on these assays, we do not consider the drawn conclusions valid. All other data in the publication including our studies to localize RZR␤ mRNA using in situ hybridization and quantitative PCR are as published. We apologize to all investigators who have spent time and effort to reproduce parts of the work using the in vitro assays described in the article.Addition submitted by Drs. Wiesenberg, Missbach, Saurat, and Carlberg: RZR␤ belongs to the RZR/ROR family of nuclear receptors (1), where the members of this family have been shown to act as ligand-independent transcription factors that bind to monomeric binding sites mediating a high constitutive transcriptional activity (2-5). Recently, Greiner et al. (6) reported failure in observing transcriptional activity of RZR␤ on monomeric sites and its modulation by melatonin. However, in some cell lines, e.g. Drosophila SL-3 cells, the constitutive activity of RZR␤ and RZR/ROR␣ can clearly be reduced, e.g. by the omission of serum to the cell culture medium (2,7,8). Under these restricted experimental conditions RZR␤ and RZR/ROR␣ reproducibly function as ligand-dependent nuclear receptors (7-10). Ligand binding assays have been performed with cells overexpressing RZR/ROR and in vitro translated RZR/ROR (7, 8), but not with the purified receptor. This suggests but does not prove that melatonin is a ligand of RZR/ROR. However, the first report of a melatonin response element in the promoter of the human 5-lipoxygenase gene (11) has demonstrated an essential role of RZR/ROR as a mediator of nuclear melatonin signaling.

Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the geneexpression pattern of 12 samples of normal appearing white matter from 10 post‐mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning. This is best illustrated by the upregulation of the transcription factors such as HIF‐1α and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1. In addition, a general neuroprotective reaction against oxidative stress is suggested. These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS. Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection. An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligondendrocyte and axonal loss.

Myelination of axons facilitates rapid impulse propagation in the nervous system. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular cause of many pathological features, including the frequently observed myelin outfoldings, remained unknown. Using label-free quantitative proteomics, we find that the presence of myelin outfoldings correlates with a loss of cytoskeletal septins in myelin. Regulated by phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2)-levels, myelin septins (SEPT2/SEPT4/SEPT7/SEPT8) and the PI(4,5)P2-adaptor anillin form previously unrecognized filaments that extend longitudinally along myelinated axons. By confocal microscopy and immunogold-electron microscopy, these filaments are localized to the non-compacted adaxonal myelin compartment. Genetic disruption of these filaments in Sept8-mutant mice causes myelin outfoldings as a very specific neuropathology. Septin filaments thus serve an important function in scaffolding the axon/myelin-unit, evidently a late stage of myelin maturation. We propose that pathological or aging-associated diminishment of the septin/anillin-scaffold causes myelin outfoldings that impair the normal nerve conduction velocity.DOI: http://dx.doi.org/10.7554/eLife.17119.001

Several novel myelin-associated/oligodendrocytic basic protein (MOBP) isoforms were identified in this study by cDNA cloning. They are small, highly basic polypeptides comprising 69, 81, and 99 amino acids (8.2, 9.7, and 11.7 kDa, respectively) and show no significant homology with described proteins or domain structures. All (as yet) identified MOBP isoforms are identical in amino acids 1-68 but differ in the length and polarity of the C-terminal region. One isoform, designated MOBP81, was shown to be expressed abundantly during development. Interestingly, MOBP81 has a significant clustering of positively charged residues at positions 69-81, a feature that also has been observed for myelin basic protein (MBP) and Po. As demonstrated by in situ hybridization, MOBP gene expression occurs during development of the rat optic nerve later than that of MBP and proteolipid protein and coincides exactly with the beginning of myelin compaction. The 2.6 kb MOBP81-A transcript is localized in the processes of oligodendrocytes, whereas the 3.8 kb MOBP81-B transcript is restricted to the perinuclear region. Therefore, MOBP81-A and related mRNAs seem to be transported to the periphery of the oligodendrocytes, as is known for the transcripts of the MBP gene. The late developmental expression of the MOBP gene suggests that the MOBP proteins act at the late steps of myelin formation, possibly in myelin compaction and in the maintenance of the myelin sheath.