The p75 Neurotrophin Receptor Mediates Neuronal Apoptosis and Is Essential for Naturally Occurring Sympathetic Neuron Death

Abstract. To determine whether the p75 neurotrophin receptor (p75NTR) plays a role in naturally occurring neuronal death, we examined neonatal sympathetic neurons that express both the TrkA tyrosine kinase receptor and p75NTR. When sympathetic neuron survival is maintained with low quantities of NGF or KCl, the neurotrophin brain-derived neurotrophic factor (BDNF), which does not activate Trk receptors on sympathetic neurons, causes neuronal apoptosis and increased phosphorylation of c-jun. Function-blocking antibody studies indicate that this apoptosis is due to BDNF-mediated activation of p75NTR. To determine the physiological relevance of these culture findings, we examined sympathetic neurons in BDNF−/− and p75NTR−/− mice. In BDNF−/− mice, sympathetic neuron number is increased relative to BDNF+/+ littermates, and in p75NTR−/− mice, the normal period of sympathetic neuron death does not occur, with neuronal attrition occurring later in life. This deficit in apoptosis is intrinsic to sympathetic neurons, since cultured p75NTR−/− neurons die more slowly than do their wild-type counterparts. Together, these data indicate that p75NTR can signal to mediate apoptosis, and that this mechanism is essential for naturally occurring sympathetic neuron death

Genomic Analysis of Mouse Retinal Development

The vertebrate retina is comprised of seven major cell types that are generated in overlapping but well-defined intervals. To identify genes that might regulate retinal development, gene expression in the developing retina was profiled at multiple time points using serial analysis of gene expression (SAGE). The expression patterns of 1,051 genes that showed developmentally dynamic expression by SAGE were investigated using in situ hybridization. A molecular atlas of gene expression in the developing and mature retina was thereby constructed, along with a taxonomic classification of developmental gene expression patterns. Genes were identified that label both temporal and spatial subsets of mitotic progenitor cells. For each developing and mature major retinal cell type, genes selectively expressed in that cell type were identified. The gene expression profiles of retinal Müller glia and mitotic progenitor cells were found to be highly similar, suggesting that Müller glia might serve to produce multiple retinal cell types under the right conditions. In addition, multiple transcripts that were evolutionarily conserved that did not appear to encode open reading frames of more than 100 amino acids in length (“noncoding RNAs”) were found to be dynamically and specifically expressed in developing and mature retinal cell types. Finally, many photoreceptor-enriched genes that mapped to chromosomal intervals containing retinal disease genes were identified. These data serve as a starting point for functional investigations of the roles of these genes in retinal development and physiology

neurogenin2 elicits the genesis of retinal neurons from cultures of nonneural cells

neurogenin2 (ngn2) encodes a basic helix–loop–helix transcription factor and plays an important role in neurogenesis from migratory neural crest cells. Its role in retinal development is poorly understood. We observed that in the developing chick retina, ngn2 was expressed in a subpopulation of proliferating progenitor cells. Ectopic expression of ngn2 in nonneural, retinal pigment epithelial cell culture triggered de novo generation of cells that expressed neural-specific markers and exhibited neuronal morphologies. Further molecular and morphological analyses showed that the main products of the induced neurogenesis were cells resembling young photoreceptor cells and cells resembling retinal ganglion cells. The generation of multiple cell types suggests that ngn2 induces various retinal pathways. Thus, unlike in the peripheral nervous system where ngn2 specifies one type of sensory neuron, ngn2 in the retina is likely involved in a common step leading to different cellular pathways. Our finding that ngn2 can instruct nonneural retinal pigment epithelial cells to differentiate toward retinal neurons demonstrates one possible way to induce de novo retinal neurogenesis

Effect of a serotonin agonist (sumatriptan) on the peptidergic innervation of the rat cerebral dura mater and on the expression of c-fos in the caudal trigeminal nucleus in an experimental migraine model

The supratentorial cerebral dura of the albino rat is equipped with a rich sensory innervation including nociceptive axons and their terminals, which display intense calcitonin gene-related peptide (CGRP) immunoreactivity both in the connective tissue and around blood vessels, Stereotactic electrical stimulation of the trigeminal (Gasserian) ganglion, regarded as an experimental migraine model, induces marked increase and disintegration of club-like perivascular CGRP-immunopositive nerve endings in the dura, Intravenous administration of sumatriptan, prior to electrical stimulation, prevents disintegration of perivascular terminals and induces accumulation of CGRP ill terminal and preterminal portions of peripheral sensory axons, Consequently, immunopositive terminals and varicosities increase in size; accumulation of axoplasmic organelles results in a ''hollow'' appearance of many varicosities, Since sumatriptan exerts its anti-migraine effect by virtue of its agonist action on 5-HT1D receptors, we suggest that sumatriptan prevents the release of CORP from dural perivascular terminals by an action at 5-HT1D receptors, In the caudal trigeminal nucleus electrical stimulation of the trigeminal ganglion induces, in interneurons, increased expression of the oncoprotein c-fos which is not prevented by intravenous application of sumatriptan. Disparate findings regarding this effect are partly due to the fact that sumatriptan very poorly passes the blood-brain barrier and partly to different experimental paradigms used by different authors. (C) 1997 Wiley-Liss, Inc

Systematic Review of the Yield of Temporal Artery Biopsy for Suspected Giant Cell Arteritis

<p>Purpose: To determine the positive yield (utility rate) of temporal artery biopsy (TAB) in patients with suspected giant cell arteritis (GCA).</p> <p>Study Design: Systematic review (CRD42017078508) and meta-regression.</p> <p>Materials and Methods: All articles concerning TAB for suspected GCA with English language abstracts from 1998 to 2017 were retrieved. Articles were excluded if they exclusively reported positive TAB, or only cases of known GCA. Where available, the pre-specified predictors of age, sex, vision symptoms, jaw claudication, duration of steroid treatment prior to TAB, specimen length, bilateral TAB, and use of ultrasound/MRI (imaging) were recorded for meta-regression.</p> <p>Results: One hundred and thirteen articles met eligibility criteria. The <i>I</i>² was 92%, and with such high heterogeneity, meta-analysis is unsuitable. The median yield of TAB was 0.25 (95% confidence interval 0.21 to 0.27), with interquartile range 0.17 to 0.34. On univariate meta-regression age (coefficient 0.012, <i>p</i> = 0.025) was the only statistically significant patient factor associated with TAB yield.</p> <p>Conclusions: Systematic review revealed high heterogeneity in the yield of TAB. The median utility rate of 25% and its interquartile range provides a benchmark for decisions regarding the under/overutilization of TAB and aids in the evaluation of non-invasive alternatives for the investigation of GCA.</p