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Markus H Schwab

Publications and source records attributed to Markus H Schwab.

8 recordsLinked to original sources
PubMed2007

Insulin-like growth factor type 1 receptor signaling in the cells of oligodendrocyte lineage is required for normal in vivo oligodendrocyte development and myelination.

Insulin-like growth factor-I (IGF-I) has been shown to be a potent agent in promoting the growth and differentiation of oligodendrocyte precursors, and in stimulating myelination during development and following injury. To definitively determine whether IGF-I acts directly on the cells of oligodendrocyte lineage, we generated lines of mice in which the type 1 IGF receptor gene (igf1r) was conditionally ablated either in Olig1 or proteolipid protein expressing cells (termed IGF1R(pre-oligo-ko) and IGF1R(oligo-ko) mice, respectively). Compared with wild type mice, IGF1R(pre-oligo-ko) mice had a decreased volume (by 35-55%) and cell number (by 54-70%) in the corpus callosum (CC) and anterior commissure at 2 and 6 weeks of age, respectively. IGF1R(oligo-ko) mice by 25 weeks of age also showed reductions, albeit less marked, in CC volume and cell number. Unlike astrocytes, the percentage of NG2(+) oligodendrocyte precursors was decreased by approximately 13% in 2-week-old IGF1R(pre-oligo-ko) mice, while the percentage of CC1(+) mature oligodendrocytes was decreased by approximately 24% in 6-week-old IGF1R(pre-oligo-ko) mice and approximately 25% in 25-week-old IGF1R(oligo-ko) mice. The reduction in these cells is apparently a result of decreased proliferation and increased apoptosis. These results indicate that IGF-I directly affects oligodendrocytes and myelination in vivo via IGF1R, and that IGF1R signaling in the cells of oligodendrocyte lineage is required for normal oligodendrocyte development and myelination. These data also provide a fundamental basis for developing strategies with the potential to target IGF-IGF1R signaling pathways in oligodendrocyte lineage cells for the treatment of demyelinating disorders.

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PubMed2006

The role of neuregulin-ErbB4 interactions on the proliferation and organization of cells in the subventricular zone.

Coordinated regulation of neuronal progenitor differentiation in the subventricular zone (SVZ) is a fundamental feature of adult neurogenesis. However, the molecular control of this process remains mostly undeciphered. Here, we investigate the role of neuregulins (NRGs) in this process and show that a NRG receptor, ErbB4, is primarily expressed by polysialylated neural cell adhesion molecule immature neuroblasts but is also detected in a subset of GFAP+ astroglial cells, ependymal cells, and Dlx2+ precursors in the SVZ. Of the NRG ligands, both NRG1 and -2 are expressed by immature polysialylated neural cell adhesion molecule neuroblasts in the SVZ. NRG2 is also expressed by some of the GFAP+ putative stem cells lining the ventricles. Infusion of exogenous NRG1 leads to rapid aggregation of Dlx2+ cells in the SVZ and affects the initiation and maintenance of organized neuroblast migration from the SVZ toward the olfactory bulb. In contrast, the infusion of NRG2 increased the number of Sox2 and GFAP+ precursors in the SVZ. An outcome of this NRG2 effect is an increase in the number of newly generated migrating neuroblasts in the rostral migratory stream and GABAergic interneurons in the olfactory bulb. The analysis of conditional null mice that lack NRG receptor, ErbB4, in the nervous system revealed that the observed activities of NRG2 require ErbB4 activation. These results indicate that different NRG ligands affect distinct populations of differentiating neural precursors in the neurogenic regions of the mature forebrain. Furthermore, these studies identify NRG2 as a factor capable of promoting SVZ proliferation, leading to the formation of new neurons in vivo.

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PubMed2006

Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice.

Conditional mutagenesis permits the cell type-specific analysis of gene functions in vivo. Here, we describe a mouse line that expresses Cre recombinase under control of regulatory sequences of NEX, a gene that encodes a neuronal basic helix-loop-helix (bHLH) protein. To mimic endogenous NEX expression in the dorsal telencephalon, the Cre recombinase gene was targeted into the NEX locus by homologous recombination in ES cells. The Cre expression pattern was analyzed following breeding into different lines of lacZ-indicator mice. Most prominent Cre activity was observed in neocortex and hippocampus, starting from around embryonic day 11.5. Within the dorsal telencephalon, Cre-mediated recombination marked pyramidal neurons and dentate gyrus mossy and granule cells, but was absent from proliferating neural precursors of the ventricular zone, interneurons, oligodendrocytes, and astrocytes. Additionally, we identified formerly unknown domains of NEX promoter activity in mid- and hindbrain. The NEX-Cre mouse will be a valuable tool for behavioral research and the conditional inactivation of target genes in pyramidal neurons of the dorsal telencephalon.

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PubMed2005

Cre/loxP-mediated inactivation of the bHLH transcription factor gene NeuroD/BETA2.

NeuroD/Beta2 is a basic helix-loop-helix (bHLH) transcription factor with important functions during development of the pancreas and the nervous system. NeuroD null mutant mice die perinatally due to diabetes caused by impaired differentiation of pancreatic endocrine cells. Additionally, null mutants display severe defects in the formation of cerebellar and hippocampal granule cells, inner ear sensory neurons, and retinal photoreceptor cells. For spatio-temporally restricted inactivation of the NeuroD gene, we generated conditional mouse mutants by flanking the NeuroD coding region with loxP sites. Homozygous NeuroD(loxP) mutant mice are fully viable and express normal levels of NeuroD mRNA and protein. Breeding NeuroD(loxP) mice to Tg(malpha6-Cre)B1LFR mice that express Cre recombinase under control of the GABA(A) receptor alpha6 subunit promoter resulted in efficient inactivation of the NeuroD gene in post-migratory cerebellar granule cells and a subset of brainstem nuclei. The NeuroD(loxP) mouse mutant will be a valuable tool to study the developmental and adult function of NeuroD in nervous system and pancreas.

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PubMed2004

Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain.

Neural progenitor proliferation, differentiation and migration are continually active in the rostral migratory stream of the adult brain. Here, we show that the receptor tyrosine kinase ErbB4 is expressed prominently by the neuroblasts present in the subventricular zone and the rostral migratory stream. The neuregulins (NRG1-NRG3), which have been identified as ErbB4 ligands, are detected either in the stream or in adjacent regions. Mice deficient in ErbB4 expressed under the control of either the nestin or the hGFAP promoter have altered neuroblast chain organization and migration and deficits in the placement and differentiation of olfactory interneurons. These findings suggest that ErbB4 activation helps to regulate the organization of neural chains that form the rostral migratory stream and influences the differentiation of olfactory interneuronal precursors.

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PubMed2004

Axonal neuregulin-1 regulates myelin sheath thickness.

In the nervous system of vertebrates, myelination is essential for rapid and accurate impulse conduction. Myelin thickness depends on axon fiber size. We use mutant and transgenic mouse lines to show that axonal Neuregulin-1 (Nrg1) signals information about axon size to Schwann cells. Reduced Nrg1 expression causes hypomyelination and reduced nerve conduction velocity. Neuronal overexpression of Nrg1 induces hypermyelination and demonstrates that Nrg1 type III is the responsible isoform. We suggest a model by which myelin-forming Schwann cells integrate axonal Nrg1 signals as a biochemical measure of axon size.

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PubMed2004

Neuregulin-2 is synthesized by motor neurons and terminal Schwann cells and activates acetylcholine receptor transcription in muscle cells expressing ErbB4.

Acetylcholine receptor (AChR) genes are transcribed selectively in synaptic nuclei of skeletal muscle fibers, leading to accumulation of the mRNAs encoding AChR subunits at synaptic sites. The signals that regulate synapse-specific transcription remain elusive, though Neuregulin-1 is considered a favored candidate. Here, we show that motor neurons and terminal Schwann cells express neuregulin-2, a neuregulin-1-related gene. In skeletal muscle, Neuregulin-2 protein is concentrated at synaptic sites, where it accumulates adjacent to terminal Schwann cells. Neuregulin-2 stimulates AChR transcription in cultured myotubes expressing ErbB4, as well as ErbB3 and ErbB2, but not in myotubes expressing only ErbB3 and ErbB2. Thus, Neuregulin-2 is a candidate for a signal that regulates synaptic differentiation.

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