Nataša Jovanov Milošević

Complex patterns and simple architects: molecular guidance cues for developing axonal pathways in the telencephalon

The aim of this review is to discuss the current research on the spatio-temporal distribution and function of the four major classes of axonal guidance cues (netrins, semaphorins, slits, and ephrins) and their receptors in the developing mammalian telencephalon. In the first part, we briefly describe guidance molecules and their receptors. In the second part, we review their overlapping distribution in the specific architectonic zones of the cerebral wall during the embryonic and early postnatal period. In the third part, we describe complementary and/or overlapping functions of these molecules in the development of all major classes of telencephalic axon pathways: subcortical (thalamic and extrathalamic) afferent systems, corticofugal (projection) systems, and cortico-cortical (commissural and ipsilateral) fiber systems. To conclude, we discuss several general themes which emerge from the current research, and point out that most axonal guidance cues have other developmental roles as well, including possible involvement in synaptic plasticity in the adult brain.

Nop2 is expressed during proliferation of neural stem cells and in adult mouse and human brain.

The nucleolar protein 2 gene encodes a protein specific for the nucleolus. It is assumed that it plays a role in the synthesis of ribosomes and regulation of the cell cycle. Due to its link to cell proliferation, higher expression of Nop2 indicates a worse tumor prognosis. In this work we used Nop2(gt1gaj) gene trap mouse strain. While lethality of homozygous animals suggested a vital role of this gene, heterozygous animals allowed the detection of expression of Nop2 in various tissues, including mouse brain. Histochemistry, immunohistochemistry and immunoelectron microscopy techniques, applied to a mature mouse brain, human brain and on mouse neural stem cells revealed expression of Nop2 in differentiating cells, including astrocytes, as well as in mature neurons. Nop2 was detected in various regions of mouse and human brain, mostly in large pyramidal neurons. In the human, Nop2 was strongly expressed in supragranular and infragranular layers of the somatosensory cortex and in layer III of the cingulate cortex. Also, Nop2 was detected in CA1 and the subiculum of the hippocampus. Subcellular analyses revealed predominant location of Nop2 within the dense fibrillar component of the nucleolus. To test if Nop2 expression correlates to cell proliferation occurring during tissue regeneration, we induced strokes in mice by middle cerebral artery occlusion. Two weeks after stroke, the number of Nop2/nestin double positive cells in the region affected by ischemia and the periventricular zone substantially increased. Our findings suggest a newly discovered role of Nop2 in both mature neurons and in cells possibly involved in the regeneration of nervous tissue.

Neural ECM in laminar organization and connectivity development in healthy and diseased human brain.

The neural extracellular matrix (ECM) provides a supportive framework for differentiating cells and their processes and regulates morphogenetic events by spatially and temporally relevant localization of signaling molecules and by direct signaling via receptor and/or coreceptor-mediated action. The embryonic human brain and fetal human brain contain large amounts and a diversity of extracellular matrix components, which are especially prominent in the transient subplate zone, in the crossroads of axonal pathways, at the developing cortical-white matter interface, and in the marginal zone. Perinatal and postnatal reorganizations of these tissue compartments extend into the second year of life. Developmental changes in the amount and composition of the extracellular matrix (as well as changes in fiber architectonics) are significant for plastic responses to damage and for changes in magnetic resonance imaging (MRI) signal intensity of the fetal and early postnatal human brain. In this chapter, we discuss the expression pattern of the major components of the fetal ECM of the human brain and the role they play during laminar and connectivity development in healthy brain and in the neurodevelopmental disorders. The aim of the chapter is to elucidate ECM-related developmental events as potential models of successful functional recovery after injury and to explore its relevance for diagnostic and therapeutic approaches.

Neuroplastin Expression in the Hippocampus of Mice Lacking Complex Gangliosides

We report changes in neuroplastin gene and protein expression in the hippocampus of B4galnt1 null mice, which lacks complex ganglioside structures, compared with that of wild-type mice. Neuroplastin mRNA expression was significantly higher in the hippocampi of B4galnt1 null mice than in wild-type mice. Moreover, Western blot analysis shows increased neuroplastin protein levels of neuroplastin-55 isoform in B4galnt1 null hippocampal homogenates. Immunohistochemistry revealed a substantially different distribution of neuroplastin immunoreactivity in sagittal sections of the hippocampi derived from B4galnt1 null in comparison with those from wild-type mice. Most strikingly, B4galnt1 null mice had relatively little neuroplastin immunoreactivity in the pyramidal layer of CA1 and CA3, whereas wild-type mice had strong neuroplastin staining of pyramidal cells. Results of this study support the hypothesis that alterations of brain ganglioside expression influence the expression of neuroplastin. As both neuroplastin and gangliosides have important roles in synaptic transmission, synaptic plasticity, and neurite outgrowth, it will be of particular interest to unravel the molecular mechanisms underlying the relationship between ganglioside composition and neuroplastin transcript and protein expression in the mammalian nervous system.

Neuroplastin deletion in glutamatergic neurons impairs selective brain functions and calcium regulation: implication for cognitive deterioration

The cell adhesion molecule neuroplastin (Np) is a novel candidate to influence human intelligence. Np-deficient mice display complex cognitive deficits and reduced levels of Plasma Membrane Ca2+ ATPases (PMCAs), an essential regulator of the intracellular Ca2+ concentration ([iCa2+]) and neuronal activity. We show abundant expression and conserved cellular and molecular features of Np in glutamatergic neurons in human hippocampal-cortical pathways as characterized for the rodent brain. In Nptnlox/loxEmx1Cre mice, glutamatergic neuron-selective Np ablation resulted in behavioral deficits indicating hippocampal, striatal, and sensorimotor dysfunction paralleled by highly altered activities in hippocampal CA1 area, sensorimotor cortex layers I-III/IV, and the striatal sensorimotor domain detected by single-photon emission computed tomography. Altered hippocampal and cortical activities correlated with reduction of distinct PMCA paralogs in Nptnlox/loxEmx1Cre mice and increased [iCa2+] in cultured mutant neurons. Human and rodent Np enhanced the post-transcriptional expression of and co-localized with PMCA paralogs in the plasma membrane of transfected cells. Our results indicate Np as essential for PMCA expression in glutamatergic neurons allowing proper [iCa2+] regulation and normal circuit activity. Neuron-type-specific Np ablation empowers the investigation of circuit-coded learning and memory and identification of causal mechanisms leading to cognitive deterioration.