Directional Guidance of Oligodendroglial Migration by Class 3 Semaphorins and Netrin-1

Spassky, Nathalie; Castro, Fernando de; Bras, Barbara Le; Heydon, Katharina; Quéraud-LeSaux, Françoise; Bloch‐Gallego, Evelyne; Chédotal, Alain; Zalc, Bernard; Thomas, Jean‐Léon

doi:10.1523/jneurosci.22-14-05992.2002

Cited by 227 publications

(195 citation statements)

References 64 publications

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“…Among up-regulated TFs (Table 4), IADGs for TSs, lipid biosynthesis, and transcriptional repression were more often correlated with NFT scores. Further, up-regulation of semaphorins (SEMA3B) and axonal semaphorin receptors (plexinB2 and ESDN), which mediate growth cone collapse and axonal retraction and guide OG migration (76)(77)(78), were correlated with NFT scores (Table 6). In contrast, TFs for growth (Table 4) and genes related to adhesion and inflammation were more often correlated with MMSE.…”

Section: Discussionmentioning

confidence: 99%

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Blalock

Geddes

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

944

853

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The pathogenesis of incipient Alzheimer's disease (AD) has been resistant to analysis because of the complexity of AD and the overlap of its early-stage markers with normal aging. Gene microarrays provide new tools for addressing complexity because they allow overviews of the simultaneous activity of multiple cellular pathways. However, microarray data interpretation is often hindered by low statistical power, high false positives or false negatives, and by uncertain relevance to functional endpoints. Here, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These well powered tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20). Biological process categories associated with incipient AD-correlated genes were identified statistically (EASE program) and revealed up-regulation of many transcription factor͞signaling genes regulating proliferation and differentiation, including tumor suppressors, oligodendrocyte growth factors, and protein kinase A modulators. In addition, up-regulation of adhesion, apoptosis, lipid metabolism, and initial inflammation processes occurred, and down-regulation of protein folding͞me-tabolism͞transport and some energy metabolism and signaling pathways took place. These findings suggest a new model of AD pathogenesis in which a genomically orchestrated up-regulation of tumor suppressor-mediated differentiation and involution processes induces the spread of pathology along myelinated axons. A lzheimer's disease (AD) has received intense study during past decades. Multiple processes have been implicated in AD, notably including abnormal ␤-amyloid (A␤) production (1-7), tau hyperphosphorylation and neurofibrillary tangles (NFTs) (8, 9), synaptic pathology (10-12), oxidative stress (13-15), inflammation (5, 16-19), protein processing or misfolding (20, 21), calcium dyshomeostasis (15,(20)(21)(22)(23)(24)(25)(26), aberrant reentry of neurons into the cell cycle (27, 28), cholesterol synthesis (29, 30), and effects of hormones (23, 31) or growth factors (17, 32). Nevertheless, the pathogenic factors that initiate these processes remain elusive.Several reasons account for the substantial resistance of AD pathogenesis to analysis. One is the vast extent and complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Another is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging, mild cognitive impairment, or incipient AD (33-35).We addressed the proble...

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Section: Discussionmentioning

confidence: 99%

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Blalock

Geddes

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

944

853

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“…Various cytokines and growth factors, such as platelet derived growth factor [258,259], fibroblast growth factor 2 [260], class 3 semaphorins [261,262], Sonic hedgehog [263], stem cell factor [264], the chemokine stromal derived factor 1 (CXCL12) [265][266][267][268][269], epidermal growth factor [270], and vascular endothelial growth factor [271] increased the migration of progenitor cells of the oligodendrocyte or neuronal lineages in vitro, and were implicated in CNS development in vivo. Very little is known, however, on the molecular signals that control neural stem and progenitor cell migration in inflammation.…”

Section: Route Of Cell Deliverymentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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“…Netrin-1 can attract several classes of axons throughout the developing nervous system but also acts as a repulsive factor for some axons. 135 In addition, netrin-1 controls neuronal migration in the developing and adult brain 136 and the migration of pancreatic progenitors, 137 neural crest cells, 138 oligodendrocyte progenitors 139,140 and endothelial cells (see below). In the adult mouse brain, netrin-1 is expressed by some neurons and myelinating oligodendrocytes.…”

Section: Netrins and Their Receptorsmentioning

confidence: 99%

The brain within the tumor: new roles for axon guidance molecules in cancers

2005

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Slits, semaphorins and netrins are three families of proteins that can attract or repel growing axons and migrating neurons in the developing nervous system of vertebrates and invertebrates. Recent studies have shown that they are widely expressed outside the nervous system and that they may play important roles in cancers. Several of the genes encoding these proteins are localized on chromosomal region associated with frequent loss-of-heterozygosity in tumors and cancer cell lines and there is also significant hypermethylation of their promoter suggesting that they may act as tumor suppressors. In addition, proteins in all these families and their receptors appear to control the vascularization of the tumors. Last, many axon guidance molecules also regulate cell migration and apoptosis in normal and tumorigenic tissues. Overall, this suggests that molecules that could mimick or block the activity of axon guidance molecules may be used as therapeutic agents for the treatment of malignancy.

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Directional Guidance of Oligodendroglial Migration by Class 3 Semaphorins and Netrin-1

Cited by 227 publications

References 64 publications

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Cell Therapy for Multiple Sclerosis

The brain within the tumor: new roles for axon guidance molecules in cancers

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