Radial glial cells as neuronal precursors: a new perspective on the correlation of morphology and lineage restriction in the developing cerebral cortex of mice

Götz, Magdalena; Hartfuss, Eva; Malatesta, Paolo

doi:10.1016/s0361-9230(01)00777-8

Cited by 210 publications

(158 citation statements)

References 76 publications

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“…More recently, radial glia were shown to divide asymmetrically to replenish themselves and at the same time produce neural progenitor cells that stain positively for brain lipid-binding protein (BLBP), glial acid fibrillary protein (GFAP), vimentin, and nestin (16,17). At E18.5, we found cells staining for these markers that followed the severity of the phenotype (e.g., Fig.…”

Section: Loss Of Mef2c Affects Distribution Of Postmitotic Neurons Ramentioning

confidence: 66%

Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo

Radford

Ragusa

et al. 2008

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

234

230

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Emerging evidence suggests that myocyte enhancer factor 2 (MEF2) transcription factors act as effectors of neurogenesis in the brain, with MEF2C the predominant isoform in developing cerebrocortex. Here, we show that conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size. NSC proliferation and survival were not affected. Conditional null mice surviving to adulthood manifested more immature electrophysiological network properties and severe behavioral deficits reminiscent of Rett syndrome, an autism-related disorder. Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex.neurogenesis ͉ synaptogenesis ͉ autism ͉ Rett syndrome K nockdown of the transcription factor MEF2C in mature cerebrocortical neurons results in increased synaptic number and activity (1). To facilitate analysis of MEF2C function in early neuronal development, we engineered a conditional knockout in NSCs by crossing floxed Mef2c mice with Nestin-Cre mice. In contrast to the findings in more mature neurons, we found a striking alteration in the distribution of new neurons in the neocortex and the opposite effect on synaptic activity, i.e., decreased neurotransmission persisting into adulthood.MEF2C belongs to the myocyte enhancer factor 2 (MEF2) subfamily of the MADS (MCM1-agamous-deficiens-serum response factor) gene family (2, 3). We cloned MEF2C from developing mouse brain, and Eric Olson and colleagues then discovered it in the heart (2, 4, 5). In cerebrocortex, MEF2 transcriptional activity is restricted to differentiated cortical neurons in a specific laminar pattern, and its distribution increases along the rostrocaudal axis (2, 4, 6). These features led to speculation on the potential role of MEF2C in the architechtonics of the cerebral cortex (2). Previous studies demonstrated an important role for MEF2C in heart development (7). In the CNS, MEF2C is involved in neuronal apoptosis (8) and synapse formation (1, 9) in vitro or in brain slices. Most recently, our laboratory discovered that a constitutively active form of MEF2C induces embryonic stem cells to commit to a neuronal fate in a virtually exclusive fashion (10). However, studies on the effect of endogenous MEF2C on CNS neurons in vivo were impeded by the embryonic lethality of conventional Mef2c-null mice because of cardiovascular defects at embryonic day (E) 9.5, before brain development (7). Here, we report that conditionally knocking out the Mef2c gene in neural progenitors causes abnormal aggregation and compaction of neurons migrating into the lower layers of the neocortex during development. Knockout mice surviving to adulthood manifest smaller, apparently less mature neurons and smaller whole brain size, with resultant aberrant electrophysiology and behavior.

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Section: Loss Of Mef2c Affects Distribution Of Postmitotic Neurons Ramentioning

confidence: 66%

Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo

Radford

Ragusa

et al. 2008

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

234

230

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“…In contrast to mammals, radial glia persist in the adult CNS of nonmammalian vertebrates (García-Verdugo et al, 2002;Kálmán, 2002;Zupanc and Clint, 2003). A prevailing view is the link between persisting radial glia and pronounced neural stem cell activity in nonmammalian vertebrates (Alvarez-Buylla et al, 2001;Götz et al, 2002). However, to our surprise, the proliferating progenitors in the cerebellum do not express canonical radial or astroglial markers, such as GFAP/ vimentin/3CB2/BLBP, but we did detect Nestin and other neural stem cell markers, indicating that they retain neuroepithelial rather than astroglial characteristics.…”

Section: Typical Glia Do Not Serve As Stem Cells In the Adult Zebrafimentioning

confidence: 99%

Stem Cells in the Adult Zebrafish Cerebellum: Initiation and Maintenance of a Novel Stem Cell Niche

Kaslin¹,

Ganz²,

Geffarth³

et al. 2009

J. Neurosci.

188

278

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In the adult CNS, neurogenesis takes place in special niches. It is not understood how these niches are formed during development and how they are maintained. In contrast to mammals, stem cell niches are abundant in zebrafish and also found in other parts of the brain than telencephalon. To understand common characteristics of neural stem cell niches in vertebrates, we studied the origin and architecture of a previously unknown stem cell niche using transgenic lines, in vivo imaging, and marker analysis. We show that bipotent stem cells are maintained in a distinct niche in the adult zebrafish cerebellum. Remarkably, the stem cells are not typical glia but instead retain neuroepithelial characteristics. The cerebellar stem cell niche is generated by the coordinated displacement of ventricle and rhombic lip progenitors in a two-step process involving morphogenetic movements and tissue growth. Importantly, the niche and its stem cells still remain in ventricular contact through a previously unknown derivative of the ventricle. Factors propagated in the ventricle are thought to be important regulators of stem cell activity. To test the requirements of one family of important factors, Fibroblast growth factors, we used zebrafish with an inducible dominant-negative Fgf receptor. Inhibition of Fgf signaling leads to significant reduction of stem cell activity. In contrast to the predominant view, adult neural stem cells in nonmammalian vertebrates show more neuroepithelial than glial characteristics. Nevertheless, retained epithelial properties such as distinct polarization and ventricular contact are critical common determinants to maintain neural stem cell activity in vertebrates.

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“…Some authors tend to consider as a fundamental landmark the induction of RC2 and the expression of BLBP mRNA (Anthony et al 2004), while others refer to the induction of the astroglial features (Gotz et al 2002;Malatesta et al 2003). These different views are probably at the root of the discrepancy between different observations about the fate of radial glial progeny (Anthony et al 2004;Malatesta et al 2003), as will be discussed in Chap.…”

Section: Time Of Appearance Of Radial Gliamentioning

confidence: 99%

“…As described in Chap. 4, however, more recent observations have compelled scholars to change this view (Anthony et al 2004;Gotz et al 2002;Malatesta et al 2000Malatesta et al , 2003Miyata et al 2001;Noctor et al 2001Noctor et al , 2004, and it is now clear that radial glia is the main source of neurons in many CNS districts.…”

Section: Time Of Appearance Of Radial Gliamentioning

confidence: 99%

Radial glia and neural stem cells

2007

Self Cite

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During the last decade, the role of radial glia has been radically revisited. Rather than being considered a mere structural component serving to guide newborn neurons towards their final destinations, radial glia is now known to be the main source of neurons in several regions of the central nervous system, notably in the cerebral cortex. Radial glial cells differentiate from neuroepithelial progenitors at the beginning of neurogenesis and share with their ancestors the bipolar shape and the expression of some molecular markers. Radial glia, however, can be distinguished from neuroepithelial progenitors by the expression of astroglial markers. Clonal analyses showed that radial glia is a heterogeneous population, comprising both pluripotent and different lineage-restricted neural progenitors. At late-embryonic and postnatal stages, radial glial cells give rise to the neural stem cells responsible for adult neurogenesis. Embryonic pluripotent radial glia and adult neural stem cells may be clonally linked, thus representing a lineage displaying stem cell features in both the developing and mature central nervous system.

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Radial glial cells as neuronal precursors: a new perspective on the correlation of morphology and lineage restriction in the developing cerebral cortex of mice

Cited by 210 publications

References 76 publications

Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo

Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo

Stem Cells in the Adult Zebrafish Cerebellum: Initiation and Maintenance of a Novel Stem Cell Niche

Radial glia and neural stem cells

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