Reelin receptors ApoER2 and VLDLR are expressed in distinct spatiotemporal patterns in developing mouse cerebral cortex

In mammalian developing brain, neuronal migration is regulated by a variety of signaling cascades, including Reelin signaling. Reelin is a glycoprotein that is mainly secreted by Cajal–Retzius neurons in the marginal zone, playing essential roles in the formation of the layered neocortex via its receptors, apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR). However, the precise mechanisms by which Reelin signaling controls the neuronal migration process remain unclear. To gain insight into how Reelin signaling controls individual migrating neurons, we generated monoclonal antibodies against ApoER2 and VLDLR and examined the localization of Reelin receptors in the developing mouse cerebral cortex. Immunohistochemical analyses revealed that VLDLR is localized to the distal portion of leading processes in the marginal zone (MZ), whereas ApoER2 is mainly localized to neuronal processes and the cell membranes of multipolar cells in the multipolar cell accumulation zone (MAZ). These different expression patterns may contribute to the distinct actions of Reelin on migrating neurons during both the early and late migratory stages in the developing cerebral cortex. J. Comp. Neurol. 523:463–478, 2015. © 2014 Wiley Periodicals, Inc.     

Cell‐specific and developmental expression of lectican‐cleaving proteases in mouse hippocampus and neocortex

Mounting evidence has demonstrated that a specialized extracellular matrix exists in the mammalian brain and that this glycoprotein‐rich matrix contributes to many aspects of brain development and function. The most prominent supramolecular assemblies of these extracellular matrix glycoproteins are perineuronal nets, specialized lattice‐like structures that surround the cell bodies and proximal neurites of select classes of interneurons. Perineuronal nets are composed of lecticans, a family of chondroitin sulfate proteoglycans that includes aggrecan, brevican, neurocan, and versican. These lattice‐like structures emerge late in postnatal brain development, coinciding with the ending of critical periods of brain development. Despite our knowledge of the presence of lecticans in perineuronal nets and their importance in regulating synaptic plasticity, we know little about the development or distribution of the extracellular proteases that are responsible for their cleavage and turnover. A subset of a large family of extracellular proteases (called a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTS]) is responsible for endogenously cleaving lecticans. We therefore explored the expression pattern of two aggrecan‐degrading ADAMTS family members, ADAMTS15 and ADAMTS4, in the hippocampus and neocortex. Here, we show that both lectican‐degrading metalloproteases are present in these brain regions and that each exhibits a distinct temporal and spatial expression pattern. Adamts15 mRNA is expressed exclusively by parvalbumin‐expressing interneurons during synaptogenesis, whereas Adamts4 mRNA is exclusively generated by telencephalic oligodendrocytes during myelination. Thus, ADAMTS15 and ADAMTS4 not only exhibit unique cellular expression patterns but their developmental upregulation by these cell types coincides with critical aspects of neural development. J. Comp. Neurol. 523:629–648, 2015. © 2014 Wiley Periodicals, Inc.     

Light‐evoked S‐nitrosylation in the retina

Nitric oxide (NO) synthesis in the retina is triggered by light stimulation. NO has been shown to modulate visual signal processing at multiple sites in the vertebrate retina, via activation of the most sensitive target of NO signaling, soluble guanylate cyclase. NO can also alter protein structure and function and exert biological effects directly by binding to free thiol groups of cysteine residues in a chemical reaction called S‐nitrosylation. However, in the central nervous system, including the retina, this reaction has not been considered to be significant under physiological conditions. Here we provide immunohistochemical evidence for extensive S‐nitrosylation that takes place in the goldfish and mouse retinas under physiologically relevant light intensities, in an intensity‐dependent manner, with a strikingly similar pattern in both species. Pretreatment with N‐ethylmaleimide (NEM), which occludes S‐nitrosylation, or with 1‐(2‐trifluromethylphenyl)imidazole (TRIM), an inhibitor of neuronal NO synthase, eliminated the light‐evoked increase in S‐nitrosylated protein immunofluorescence (SNI) in the retinas of both species. Similarly, light did not increase SNI, above basal levels, in retinas of transgenic mice lacking neuronal NO synthase. Qualitative analysis of the light‐adapted mouse retina with mass spectrometry revealed more than 300 proteins that were S‐nitrosylated upon illumination, many of which are known to participate directly in retinal signal processing. Our data strongly suggest that in the retina light‐evoked NO production leads to extensive S‐nitrosylation and that this process is a significant posttranslational modification affecting a wide range of proteins under physiological conditions. J. Comp. Neurol. 523:2082–2110, 2015. © 2015 Wiley Periodicals, Inc.     

Expression of peroxiredoxins and thioredoxins in the mouse spinal cord during embryonic development

Reactive oxygen and nitrogen species (ROS/RNS) are natural byproducts of cellular metabolism. Although these molecules are deleterious at high concentrations, moderate levels of ROS/RNS are essential for normal cell function and take part in numerous cellular processes. The regulation of ROS/RNS is largely attended by peroxiredoxins (Prdxs) and their main reductants, thioredoxins (Trxs). Through their oxidoreductase activities, the members of the Trx/Prdx system can also affect certain cellular processes, notably many implicated in central nervous system (CNS) development. Although several studies have investigated the expression of Prdxs and Trxs in mouse, rat, and human adult CNS, few data are available concerning embryonic stages. In this work, we use immunofluorescence analyses to study the distribution of these enzymes during prenatal mouse spinal cord development. Our results highlight several patterns that contrast with available data for the adult. Indeed, Prdx1, Prdx4, and Prdx6, which are expressed in glial cells in the adult CNS, present clear neuronal localization in mouse spinal cord during embryonic development. Additionally, Prdx1, Prdx2, and to a lesser extent Prdx4, Prdx6, and Trx1 are localized mainly in the nucleus of neural cells. Finally, we identified a consistent, intense expression of all Prdxs and Trxs in groups of cells located in ventral regions of the spinal cord that express motor neuronal markers. These striking expression patterns suggest novel functions of these enzymes at these stages and offer clues to the role of the Trx/Prdx system during embryonic development of the spinal cord. J. Comp. Neurol. 523:2599–2617, 2015. © 2015 Wiley Periodicals, Inc.