STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.

Objective: Pathological findings in neonatal brain injury associated with preterm birth include focal and/or diffuse white matter injury (WMI). Despite the heterogeneous nature of this condition, reactive astrogliosis and microgliosis are frequently observed. Thus, molecular mechanisms by which glia activation contribute to WMI were investigated.

Intranasal administration of aTf protects and repairs the neonatal white matter after a cerebral hypoxic-ischemic event.

Our previous studies showed that the intracerebral injection of apotransferrin (aTf) attenuates white matter damage and accelerates the remyelination process in a neonatal rat model of cerebral hypoxia-ischemia (HI) injury. However, the intracerebral injection of aTf might not be practical for clinical treatments. Therefore, the development of less invasive techniques capable of delivering aTf to the central nervous system would clearly aid in its effective clinical use.

Golli myelin basic proteins stimulate oligodendrocyte progenitor cell proliferation and differentiation in remyelinating adult mouse brain.

Golli myelin basic proteins are necessary for normal myelination, acting via voltage and store-dependent Ca(2+) entry at multiple steps during oligodendrocyte progenitor cell (OPC) development. To date nothing is known regarding the role of golli proteins in demyelination or remyelination events. Here the effects of golli ablation and overexpression in myelin loss and recovery were examined using the cuprizone (CPZ) model of demyelination/remyelination.

Developmental activation of the proteolipid protein promoter transgene in neuronal and oligodendroglial cells of neostriatum in mice.

Prior studies suggest that non-canonical proteolipid protein (PLP) gene expression occurs during development in non-myelinating neurons as well as myelinating oligodendroglia in mammalian brain. To assess this possibility in neostriatum, a region of uncertain PLP gene expression in neurons, morphological and electrophysiological tools were used to determine phenotypes of cells with activation of a PLP promoter transgene during the early postnatal period in mice. PLP gene expression is evident in both neuronal and oligodendroglial phenotypes in developing neostriatum, a conclusion based on three novel observations: (1) An enhanced green fluorescent protein (EGFP) reporter of PLP promoter activation was localized in two distinct populations of cells, which exhibit collective, developmental differences of morphological and electrophysiological characteristics in accord with neuronal and oligodendroglial phenotypes of neostriatal cells found during the early postnatal period in both transgenic and wild-type mice.

Modulation of canonical transient receptor potential channel 1 in the proliferation of oligodendrocyte precursor cells by the golli products of the myelin basic protein gene.

Golli proteins, products of the myelin basic protein gene, function as a new type of modulator of intracellular Ca(2+) levels in oligodendrocyte progenitor cells (OPCs). Because of this, they affect a number of Ca(2+)-dependent functions, such as OPC migration and process extension. To examine further the Ca(2+) channels regulated by golli, we studied the store-operated Ca(2+) channels (SOCCs) in OPCs and acute brain slice preparations from golli knock-out and golli-overexpressing mice.

Classical 18.5-and 21.5-kDa isoforms of myelin basic protein inhibit calcium influx into oligodendroglial cells, in contrast to golli isoforms.

The myelin basic protein (MBP) family arises from different transcription start sites of the golli (gene of oligodendrocyte lineage) complex, with further variety generated by differential splicing. The "classical" MBP isoforms are peripheral membrane proteins that facilitate compaction of the mature myelin sheath but also have multiple protein interactions. The early developmental golli isoforms have previously been shown to promote process extension and enhance Ca(2+) influx into primary and immortalized oligodendrocyte cell lines.

Vasoactive intestinal peptide loss leads to impaired CNS parenchymal T-cell infiltration and resistance to experimental autoimmune encephalomyelitis.

The neuropeptide vasoactive intestinal peptide (VIP) has been shown to inhibit macrophage proinflammatory actions, promote a positive Th2/Th1 balance, and stimulate regulatory T-cell production. The fact that this peptide is highly efficacious in animal models of inflammatory diseases such as collagen-induced arthritis and experimental autoimmune encephalomyelitis (EAE) suggests that the endogenous peptide might normally provide protection against such pathologies. We thus studied the response of VIP-deficient (i.

The Gli3 hypomorphic mutation Pdn causes selective impairment in the growth, patterning, and axon guidance capability of the lateral ganglionic eminence.

Previous studies have defined a requirement for Sonic hedgehog (Shh) signaling in patterning the ventral telencephalon, a major source of the neuronal diversity found in the mature telencephalon. The zinc finger transcription factor Gli3 is a critical component of the Shh signaling pathway and its loss causes major defects in telencephalic development. Gli3 is expressed in a graded manner along the dorsoventral axis of the telencephalon but it is unknown whether Gli3 expression levels are important for dorsoventral telencephalic patterning.

Regulation of L-type Ca++ currents and process morphology in white matter oligodendrocyte precursor cells by golli-myelin proteins.

The golli myelin basic proteins are expressed in oligodendroglial precursor cells (OPCs) where they play a role in regulating Ca(2+) homeostasis. During depolarization, they influence process outgrowth and migration through their action on voltage-operated Ca(2+) channels (VOCCs). To identify ion channels that are modulated by golli, we examined the electrophysiological properties of VOCCs in OPCs in the white matter of golli knock-out and control mice.

Multiple kinase pathways regulate voltage-dependent Ca2+ influx and migration in oligodendrocyte precursor cells.

It is becoming increasingly clear that voltage-operated Ca(2+) channels (VOCCs) play a fundamental role in the development of oligodendrocyte progenitor cells (OPCs). Because direct phosphorylation by different kinases is one of the most important mechanisms involved in VOCC modulation, the aim of this study was to evaluate the participation of serine-threonine kinases and tyrosine kinases (TKs) on Ca(2+) influx mediated by VOCCs in OPCs. Calcium imaging revealed that OPCs exhibited Ca(2+) influx after plasma membrane depolarization via L-type VOCCs.

The multiple roles of myelin protein genes during the development of the oligodendrocyte.

It has become clear that the products of several of the earliest identified myelin protein genes perform functions that extend beyond the myelin sheath. Interestingly, these myelin proteins, which comprise proteolipid protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase and the classic and golli MBPs (myelin basic proteins), play important roles during different stages of oligodendroglial development. These non-myelin-related functions are varied and include roles in the regulation of process outgrowth, migration, RNA transport, oligodendrocyte survival and ion channel modulation.

Targeted overexpression of a golli-myelin basic protein isoform to oligodendrocytes results in aberrant oligodendrocyte maturation and myelination.

Recently, several in vitro studies have shown that the golli-myelin basic proteins regulate Ca2+ homoeostasis in OPCs (oligodendrocyte precursor cells) and immature OLs (oligodendrocytes), and that a number of the functions of these cells are affected by cellular levels of the golli proteins. To determine the influence of golli in vivo on OL development and myelination, a transgenic mouse was generated in which the golli isoform J37 was overexpressed specifically within OLs and OPCs. The mouse, called JOE (J37-overexpressing), is severely hypomyelinated between birth and postnatal day 50.

Regulation of store-operated and voltage-operated Ca2+ channels in the proliferation and death of oligodendrocyte precursor cells by golli proteins.

OPCs (oligodendrocyte precursor cells) express golli proteins which, through regulation of Ca2+ influx, appear to be important in OPC process extension/retraction and migration. The aim of the present study was to examine further the role of golli in regulating OPC development. The effects of golli ablation and overexpression were examined in primary cultures of OPCs prepared from golli-KO (knockout) and JOE (golli J37-overexpressing) mice.

Golli myelin basic proteins regulate oligodendroglial progenitor cell migration through voltage-gated Ca2+ influx.

Migration of oligodendrocyte progenitor cells (OPCs) from proliferative zones to their final location in the brain is an essential step in nervous system development. Golli proteins, products of the myelin basic protein gene, can modulate voltage-gated Ca(2+) uptake in OPCs during process extension and retraction. Given the importance of process extension/retraction on movement, the consequences of golli expression on OPC migration were examined in vivo and in vitro using time-lapse imaging of isolated OPCs and acute brain slice preparations from golli KO and golli J37 overexpressing mice (JOE).

Dynamic integration of subplate neurons into the cortical barrel field circuitry during postnatal development in the Golli-tau-eGFP (GTE) mouse.

In the Golli-tau-eGFP (GTE) transgenic mouse the reporter gene expression is largely confined to the layer of subplate neurons (SPn), providing an opportunity to study their intracortical and extracortical projections. In this study, we examined the thalamic afferents and layer IV neuron patterning in relation to the SPn neurites in the developing barrel cortex in GTE mouse at ages embryonic day 17 (E17) to postnatal day 14 (P14). Serotonin transporter immunohistochemistry or cytochrome oxydase histochemistry was used to reveal thalamic afferent patterning.

Genes involved in the formation of the earliest cortical circuits.

Building the brain is like erecting a house of cards. The early connections provide the foundation of the adult structure, and disruption of these may be the source of many developmental flaws. Cerebral cortical developmental disorders (including schizophrenia and autism) and perinatal injuries involve cortical neurons with early connectivity.

Increased expression of golli myelin basic proteins enhances calcium influx into oligodendroglial cells.

The myelin basic protein (MBP) gene encodes two families of proteins: the classic MBP constituents of myelin and the golli-MBPs, the function of which is less well understood. Previous work suggests that golli proteins may play a role in Ca2+ homeostasis in oligodendrocytes (OLs) and in T-cells. Overexpression of golli in OL cell lines induces elaboration of sheets and processes.

Visualization of corticofugal projections during early cortical development in a tau-GFP-transgenic mouse.

The first postmitotic neurons in the developing neocortex establish the preplate layer. These early-born neurons have a significant influence on the circuitry of the developing cortex. However, the exact timing and trajectory of their projections, between cortical hemispheres and intra- and extra-cortical regions, remain unresolved.

T(2)-weighted microMRI and evoked potential of the visual system measurements during the development of hypomyelinated transgenic mice.

Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.

Golli protein negatively regulates store depletion-induced calcium influx in T cells.

Calcium influx is crucial for T cell activation and differentiation. The detailed regulation of this process remains unclear. We report here that golli protein, an alternatively spliced product of the myelin basic protein gene, plays a critical role in regulating calcium influx in T cells.

Region-specific myelin pathology in mice lacking the golli products of the myelin basic protein gene.

The myelin basic protein (MBP) gene encodes two families of proteins, the classic MBP constituents of myelin and the golli-MBPs, the function of which is less well understood. In this study, targeted ablation of the golli-MBPs, but not the classic MBPs, resulted in a distinct phenotype unlike that of knock-outs (KOs) of the classic MBPs or other myelin proteins. Although the golli KO animals did not display an overt dysmyelinating phenotype, they did exhibit delayed and/or hypomyelination in selected areas of the brain, such as the visual cortex and the optic nerve, as determined by Northern and Western blots and immunohistochemical analysis with myelin protein markers.

Overexpression of human transferrin in two oligodendroglial cell lines enhances their differentiation.

We have previously demonstrated that the addition of apotransferrin (aTf) to oligodendroglial cell (OLGc) primary cultures accelerates their maturation. Cells treated with aTf developed a multipolar morphology and displayed increased expression of mature OLGc markers. In this work, we studied the effect of Tf overexpression in two OLGc lines, N19 and N20.

The golli-myelin basic protein negatively regulates signal transduction in T lymphocytes.

Protein kinase C (PKC) plays a critical role in signal transduction controlling T lymphocyte activation. Both positive and negative regulation of signal transduction is needed for proper control of T lymphocyte activation. We have found that a golli product of the myelin basic protein (MBP) gene can serve as a negative regulator of signaling pathways in the T lymphocyte, particularly the PKC pathway.

Embryonic expression of the soma-restricted products of the myelin proteolipid gene in motor neurons and muscle.

In addition to classic proteolipid protein (PLP) and DM20, the mouse myelin proteolipid gene produces the sr-PLP and sr-DM20 proteins. The sr-isoforms are localized to the cell bodies of both oligodendrocytes and neurons. However, they are expressed to a greater extent in neurons than they are in glia.

Apotransferrin promotes the differentiation of two oligodendroglial cell lines.

We have previously shown that addition of apotransferrin (aTf) accelerates maturation of oligodendroglial cells (OLGcs) in primary cultures. In this work, we examined the effect of aTf on two conditionally immortalized cell lines: N19 and N20.1.