RGD Reference Report - Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. - Rat Genome Database

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Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis.

Authors: Wang, Yue  Imitola, Jaime  Rasmussen, Stine  O'Connor, Kevin C  Khoury, Samia J 
Citation: Wang Y, etal., Ann Neurol. 2008 Oct;64(4):417-27. doi: 10.1002/ana.21457.
RGD ID: 12801440
Pubmed: PMID:18991353   (View Abstract at PubMed)
PMCID: PMC2757750   (View Article at PubMed Central)
DOI: DOI:10.1002/ana.21457   (Journal Full-text)


OBJECTIVE: Neurovascular niches have been proposed as critical components of the neural stem cell (NSC) response to acute central nervous system injury; however, it is unclear whether these potential reparative niches remain functional during chronic injury. Here, we asked how central nervous system inflammatory injury regulates the intrinsic properties of NSCs and their niches.
METHODS: We investigated the sonic hedgehog (Shh)-Gli1 pathway, an important signaling pathway for NSCs, in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), and its regulation by inflammatory cytokines.
RESULTS: We show that Shh is markedly upregulated by reactive and perivascular astroglia in areas of injury in MS lesions and during EAE. Astroglia outside the subventricular zone niche can support NSC differentiation toward neurons and oligodendrocytes, and Shh is a critical mediator of this effect. Shh induces differential upregulation of the transcription factor Gli1, which mediates Shh-induced NSC differentiation. However, despite the increase in Shh and the fact that Gli1 was initially increased during early inflammation of EAE and active lesions of MS, Gli1 was significantly decreased in spinal cord oligodendrocyte precursor cells after onset of EAE, and in chronic active and inactive lesions from MS brain. The Th1 cytokine interferon-gamma was unique in inducing Shh expression in astroglia and NSCs, while paradoxically suppressing Gli1 expression in NSCs and inhibiting Shh-mediated NSC differentiation.
INTERPRETATION: Our data suggest that endogenous repair potential during chronic injury appears to be limited by inflammation-induced alterations in intrinsic NSC molecular pathways such as Gli1.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Gli1  (GLI family zinc finger 1)
Shh  (sonic hedgehog signaling molecule)

Genes (Mus musculus)
Gli1  (GLI-Kruppel family member GLI1)
Shh  (sonic hedgehog)

Genes (Homo sapiens)
GLI1  (GLI family zinc finger 1)
SHH  (sonic hedgehog signaling molecule)


Additional Information