Regulation of oligodendrocyte precursor migration during development, in adulthood and in pathology

Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). These cells originate from oligodendrocyte precursor cells (OPCs) during development, and they migrate extensively from oligodendrogliogenic niches along the neural tube to colonise the entire CNS. Like many other such events, this migratory process is precisely regulated by a battery of positional and signalling cues that act via their corresponding receptors and that are expressed dynamically by OPCs. Here, we will review the cellular and molecular basis of this important event during embryonic and postnatal development, and we will discuss the relevance of the substantial number of OPCs existing in the adult CNS. Similarly, we will consider the behaviour of OPCs in normal and pathological conditions, especially in animal models of demyelination and of the demyelinating disease, multiple sclerosis. The spontaneous remyelination observed after damage in demyelinating pathologies has a limited effect. Understanding the cellular and molecular mechanisms underlying the biology of OPCs, particularly adult OPCs, should help in the design of neuroregenerative strategies to combat multiple sclerosis and other demyelinating diseases.     

Glutamine synthetase activity during mouse brain development

Summary The specific activity of glutamine synthetase (GS) in mouse brain was 2-fold higher in the olfactory bulbs than in other regions. After birth, the specific activity of GS increased more rapidly in medulla oblongata and in olfactory bulbs, than in cerebral and cerebellar cortex. The activity of GS in primary cultures of brain hemispheres increased more slowly than in homogenates of whole brains. However, when astroblasts were treated in vitro with glucocorticoids or mouse brain extracts, GS activity reached 4 times the level measured in the homogenate of an adult mouse brain. We conclude that levels of GS activity may relate to the maturation of astrocytes, and propose that GS may be used as a marker of astrocytic maturation.     

Glutamine synthetase activity during mouse brain development

The specific activity of glutamine synthetase (GS) in mouse brain was 2-fold higher in the olfactory bulbs than in other regions. After birth, the specific activity of GS increased more rapidly in medulla oblongata and in olfactory bulbs, than in cerebral and cerebellar cortex. The activity of GS in primary cultures of brain hemispheres increased more slowly than in homogenates of whole brains. However, when astroblasts were treated in vitro with glucocorticoids or mouse brain extracts, GS activity reached 4 times the level measured in the homogenate of an adult mouse brain. We conclude that levels of GS activity may relate to the maturation of astrocytes, and propose that GS may be used as a marker of astrocytic maturation.     

6-azauridine in brain tissue during chick embryonal development

Résumé 10 mg d'azauridine-6 ont été injectés dans les ufs au 4è et au 8è jour d'incubation. Dans nos précédentes expériences, cette dose a provoqué des malformations dans les embryons du poulet. La concentration de l'azauridine-6 a été déterminée dans le cerveau des embryons et on a trouve qu'elle varie de 0,48–1,16 mg pour 1 g du poids sec du cerveau, du 14è au 20è jour d'incubation.     

Changes in composition of etheric lipids during brain development

Résumé On a étudié les lipides éthériques dans la capsule interne, la région interlobaire et la substance blanche du lobe pariétal et temporal. On a constaté qu'vant la myélinisation la concentration des ces lipides est supérieure dans la capsule interne tandis qu'après le lobe temporal présente la plus haute concentration par rapport aux autres régions étudiées. Ces fluctuations expriment probablement l'instabilité lipidique des membranes cellulaires se trouvant à l'extérieur de la myéline.     

Hedgehog signaling in pancreas development and disease

Since its discovery, numerous studies have shown that the Hedgehog (Hh) signaling pathway plays an instrumental role during diverse processes of cell differentiation and organ development. More recently, it has become evident that Hh signaling is not restricted to developmental events, but retains some of its activity during adult life. In mature tissues, Hh signaling has been implicated in the maintenance of stem cell niches in the brain, renewal of the gut epithelium and differentiation of hematopoietic cells. In addition to the basal function in adult tissue, deregulated signaling has been implicated in a variety of cancers, including basal cell carcinoma, glioma and small cell lung cancer. Here, we will focus on the role of Hh signaling in pancreas development and pancreatic diseases, including diabetes mellitus, chronic pancreatitis and pancreatic cancer. Received 5 August 2005; received after revision 4 November 2005; accepted 22 November 2005     

DNA and RNA in the brain of the honeybee as a function of development and age

Zusammenfassung Aus Gehirnen von Bienen verschiedener Altersstufen wurden DNS und RNS extrahiert und deren Mengen spektrophotometrisch bestimmt.

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Supported by Sandoz Stiftung zur Förderung der medizinischbiologischen Wissenschaften     

Methadone and brain development

Summary The effect of maternally administered methadone hydrochloride (5 mg/kg) on brain development of off-spring treated during gestation and/or lactation was studied in 21-day-old rats. Animals treated during gestation or lactation were the most severely affected, with reductions in brain weights (12% and 30%,respectively), and DNA values (50% and 34%, respectively) observed.The assistance of Eileen J. Zagon is gratefully acknowledged. This research was supported in part by American Cancer Society grant PDT-27B and NIDP grant DA01618-01.     

Purinergic signaling in embryonic and stem cell development

Nucleotides are of crucial importance as carriers of energy in all organisms. However, the concept that in addition to their intracellular roles, nucleotides act as extracellular ligands specifically on receptors of the plasma membrane took longer to be accepted. Purinergic signaling exerted by purines and pyrimidines, principally ATP and adenosine, occurs throughout embryologic development in a wide variety of organisms, including amphibians, birds, and mammals. Cellular signaling, mediated by ATP, is present in development at very early stages, e.g., gastrulation of Xenopus and germ layer definition of chick embryo cells. Purinergic receptor expression and functions have been studied in the development of many organs, including the heart, eye, skeletal muscle and the nervous system. In vitro studies with stem cells revealed that purinergic receptors are involved in the processes of proliferation, differentiation, and phenotype determination of differentiated cells. Thus, nucleotides are able to induce various intracellular signaling pathways via crosstalk with other bioactive molecules acting on growth factor and neurotransmitter receptors. Since normal development is disturbed by dysfunction of purinergic signaling in animal models, further studies are needed to elucidate the functions of purinoceptor subtypes in developmental processes.     

Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells

Poly(methoxypolyethyleneglycol cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to diffuse through the blood-brain barrier after intravenous administration. However, the mechanism of transport of these nanoparticles into brain has not yet been clearly elucidated. The development of a model of rat brain endothelial cells (RBEC) in culture has allowed investigations into this mechanism. A study of the intracellular trafficking of nanoparticles by cell fractionation and confocal microscopy showed that nanoparticles are internalized by the endocytic pathway. Inhibition of the caveolae-mediated pathway by preincubation with filipin and nystatin did not modify the cellular uptake of the nanoparticles. In contrast, chlorpromazine and NaN₃ pretreatment, which interferes with clathrin and energy-dependent endocytosis, caused a significant decrease of nanoparticle internalization. Furthermore, cellular uptake experiments with nanoparticles preincubated with apolipoprotein E and blocking of low-density lipoprotein receptors (LDLR) clearly suggested that the LDLR-mediated pathway was involved in the endocytosis of PEGPHDCA nanoparticles by RBEC. Received 1 September 2006; received after revision 4 December 2006; accepted 18 December 2006     

Neuronal calcium signaling: function and dysfunction

Calcium (Ca²⁺) is an universal second messenger that regulates the most important activities of all eukaryotic cells. It is of critical importance to neurons as it participates in the transmission of the depolarizing signal and contributes to synaptic activity. Neurons have thus developed extensive and intricate Ca²⁺ signaling pathways to couple the Ca²⁺ signal to their biochemical machinery. Ca²⁺ influx into neurons occurs through plasma membrane receptors and voltage-dependent ion channels. The release of Ca²⁺ from the intracellular stores, such as the endoplasmic reticulum, by intracellular channels also contributes to the elevation of cytosolic Ca²⁺. Inside the cell, Ca²⁺ is controlled by the buffering action of cytosolic Ca²⁺-binding proteins and by its uptake and release by mitochondria. The uptake of Ca²⁺ in the mitochondrial matrix stimulates the citric acid cycle, thus enhancing ATP production and the removal of Ca²⁺ from the cytosol by the ATP-driven pumps in the endoplasmic reticulum and the plasma membrane. A Na⁺/Ca²⁺ exchanger in the plasma membrane also participates in the control of neuronal Ca²⁺. The impaired ability of neurons to maintain an adequate energy level may impact Ca²⁺ signaling: this occurs during aging and in neurodegenerative disease processes. The focus of this review is on neuronal Ca²⁺ signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission. The contribution of altered Ca²⁺ signaling in the most important neurological disorders will then be considered.     

35S-Sulphate incorporation into myelin sulphated mucopolysaccharides during rat brain development

Summary Rat brain myelin acid mucopolysaccharides (AMPS) incorporate 15%, 8%, 5.5% and 4% of tojtal associated³⁵S-sulphate, 14, 21, 30 and 75 days after birth, respectively. The course of³⁵S-sulphate incorporation into total rat brain mucopolysaccharides, as well in those from myelin, had a similar feature with peak on the 2nd week and a significant decrease on the 3rd and 4th week postnatally.     

Blastomere biopsy influences epigenetic reprogramming during early embryo development,which impacts neural development and function in resulting mice

Blastomere biopsy is used in preimplantation genetic diagnosis; however, the long-term implications on the offspring are poorly characterized. We previously reported a high risk of memory defects in adult biopsied mice. Here, we assessed nervous function of aged biopsied mice and further investigated the mechanism of neural impairment after biopsy. We found that aged biopsied mice had poorer spatial learning ability, increased neuron degeneration, and altered expression of proteins involved in neural degeneration or dysfunction in the brain compared to aged control mice. Furthermore, the MeDIP assay indicated a genome-wide low methylation in the brains of adult biopsied mice when compared to the controls, and most of the genes containing differentially methylated loci in promoter regions were associated with neural disorders. When we further compared the genomic DNA methylation profiles of 7.5-days postconception (dpc) embryos between the biopsy and control group, we found the whole genome low methylation in the biopsied group, suggesting that blastomere biopsy was an obstacle to de novo methylation during early embryo development. Further analysis on mRNA profiles of 4.5-dpc embryos indicated that reduced expression of de novo methylation genes in biopsied embryos may impact de novo methylation. In conclusion, we demonstrate an abnormal neural development and function in mice generated after blastomere biopsy. The impaired epigenetic reprogramming during early embryo development may be the latent mechanism contributing to the impairment of the nervous system in the biopsied mice, which results in a hypomethylation status in their brains.     

35S-sulphate incorporation into myelin sulphated mucopolysaccharides during rat brain development.

Rat brain myelin acid mucopolysaccharides (AMPS) incorporate 15%, 8%, 5.5% and 4% of total associated 35S-sulphate, 14, 21, 30 and 75 days after birth, respectively. The course of 35S-sulphate incorporation into total rat brain mucopolysaccharides, as well in those from myelin, had a similar feature with peak on the 2nd week and a significant decrease on the 3rd and 4th week postnatally.     

ALK1 signaling in development and disease: new paradigms

Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.     

Wnt signaling: multiple functions in neural development

Wnt signaling has proven to be essential for neural development at various stages and across species. Wnts are involved in morphogenesis and patterning, and their proliferation-promoting role is a key function in stem cell maintenance and the expansion of progenitor pools. Moreover, Wnt signaling is involved in differentiation processes and lineage decision events during both central and peripheral nervous system development. Additionally, several reports point to a role of Wnt signaling in axon guidance and neurite outgrowth. This article reviews and consolidates the existing evidence for the functions of Wnt signaling in neural development.Received 10 December 2004; received after revision 19 January 2005; accepted 21 January 2005     

Changes in the G6PDH/6PGDH ratio in the chick brain during development

Summary The profile of the G6PDH/6PGDH ratio at various stages of development was drawn on the basis of the specific activities of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconic dehydrogenase (6PGDH) found in the embryonic brain of the chick. The ratio value lower than 1, found in the adult chick brain, is a special biochemical feature which emerges at a certain time-point of development, occurring around the middle of the prehatching age.Acknowledgment. This work was supported by grants from M.P.I. and C.N.R.