Glial progenitors of the neonatal subventricular zone differentiate asynchronously, leading to spatial dispersion of glial clones and to the persistence of immature glia in the adult mammalian CNS

231

217

The subventricular zone (SVZ) in the neonatal mammalian forebrain simultaneously generates olfactory interneurons, astrocytes, and oligodendrocytes. The molecular cues that enable SVZ progenitors to generate three distinct cell lineages without a temporal switching mechanism are not known. Here, we demonstrate that the basic helix-loop-helix transcription factor Olig2 plays a central role in this process. Olig2 is specifically expressed in gliogenic progenitors in the postnatal SVZ and by all glial lineages derived from this structure. By expressing normal and dominant-interfering forms of Olig2 in vivo, we show that Olig2 repressor function is both sufficient and necessary to prevent neuronal differentiation and to direct SVZ progenitors toward astrocytic and oligodendrocytic fates. Although Olig2 activity has been associated previously with motor neuron and oligodendrocyte development, our findings establish a previously unappreciated role for Olig2 in the development of astrocytes. Furthermore, these results indicate that Olig2 serves a critical role in pan-glial versus neuronal fate decisions in SVZ progenitors, making it the first intrinsic fate determinant shown to operate in the early postnatal SVZ.

Section: Svz Cell Potentialmentioning

confidence: 53%

Olig2 Directs Astrocyte and Oligodendrocyte Formation in Postnatal Subventricular Zone Cells

Marshall¹,

Novitch²,

Goldman³

2005

231

217

“…Although a few of the CLE-GFP-infected cells were GFAP positive (data not shown), the majority of the control and EGFR-expressing cells were GFAPϪ (Fig. 4 F), which indicates that these cells, at least at this early time, had not reached the stage of astrocyte development when they express GFAP (Zerlin et al, 2004). Almost all of the EGFR-GFPϩ cells were NG2ϩ (Fig.…”

Section: Egfr Overexpression In Vivo Inhibits the Final Differentiatimentioning

confidence: 89%

ConstitutiveEGFRSignaling in Oligodendrocyte Progenitors Leads to Diffuse Hyperplasia in Postnatal White Matter

Ivković

Canoll²,

Goldman³

2008

Gliogenesis requires the careful orchestration of migration, differentiation, and proliferation of progenitors. Signaling through the epidermal growth factor receptor (EGFR) has been implicated in regulating these processes in a variety of cell types, including neural progenitors. By retroviral infection, we constitutively expressed an EGFR-GFP fusion protein in white matter glial progenitors at postnatal day 3 of the rat forebrain in vivo and analyzed the development of these cells over the subsequent 15 weeks. EGFR-GFPϩ cells remained proliferative and migratory, gradually populating the brains ipsilateral and contralateral to the side of viral infection, but never differentiated into mature glia. The accumulation of these cells doubled the total cell density in white matter and led to a 10-fold increase in the abundance of glial progenitors, giving rise to a progenitor "hyperplasia." The marker profile of infected cells, NG2ϩ, olig2ϩ, PDGFR-␣ϩ, nestinϩ, GFAPϪ, and CC1Ϫ, indicated a close resemblance to oligodendrocyte progenitors. Positive immunostaining for phosphorylated EGFR colocalized with punctate accumulation of EGFR-GFP, indicating that a subset of receptors was engaged in active signaling. Furthermore, EGF was required to observe phospho-tyrosine EGFR immunostaining of glial progenitors in culture. These observations suggest that constitutive EGFR expression can inhibit glial differentiation, but requires ligand as well.

“…2). The role of SVZ cells in generating glial progenitors has been characterized extensively in the neonatal brain (Zerlin et al, 2004). It has also been demonstrated that these SVZ cells tend to reacquire this gliogenic potential in response to demyelinating conditions (Gensert and Goldman, 1997;NaitOumesmar et al, 1999;Picard-Riera et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Expression of Stathmin, a Developmentally Controlled Cytoskeleton-Regulating Molecule, in Demyelinating Disorders

Liu

Stadelmann²,

Moscarello³

et al. 2005

Understanding the biological relevance of reexpression of developmental molecules in pathological conditions is crucial for the development of new therapies. In this study, we report the increased expression of stathmin, a developmentally regulated tubulin-binding protein, in the brains of patients with multiple sclerosis (MS). In physiological conditions, stathmin immunoreactivity was observed in polysialic acid-neural cell adhesion molecule-positive migratory progenitors in the subventricular zone, and its expression progressively decreased as the cells matured into oligodendrocytes (OLs). In MS patients, however, stathmin levels were elevated in 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase-positive OLs, in 10 of 10 bioptic samples analyzed. Increased levels of stathmin were confirmed by Western blot analysis of normal-appearing white matter samples from MS brains. In addition, using mass spectrometry, stathmin was identified as the main component of a specific myelin protein fraction consistently increased in MS preparations compared with controls.To test the biological relevance of increased stathmin levels, primary OL progenitors were transfected using a myc-tagged stathmin cDNA and were allowed to differentiate. Consistent with a distinct role played by this molecule in cells of the OL lineage at different developmental stages, transient transfection in progenitors favored the bipolar migratory phenotype but did not affect survival. However, sustained stathmin levels in differentiating OLs, because of overexpression, resulted in enhanced apoptotic susceptibility.We conclude that stathmin expression in demyelinating disorders could have a dual role. On one hand, by favoring the migratory phenotype of progenitors, it may promote myelin repair. On the other hand, stathmin in mature OLs may indicate cell stress and possibly affect survival.