The Transcription Factor, Pax6, is Required for Cell Proliferation and Differentiation in the Developing Cerebral Cortex

Warren, Natasha; Carić, Damira; Pratt, Thomas; Clausen, Julia A.; Asavaritikrai, Pundit; Mason, John O.; Hill, Robert E.; Price, David J.

doi:10.1093/cercor/9.6.627

Cited by 155 publications

(128 citation statements)

References 47 publications

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“…Other proteins have been shown to directly regulate proliferation/differentiation of PCs and the timing of neurogenesis (Caric et al, 1997;Warren et al, 1999;Fukuda et al, 2000). However, the molecular mechanisms regulating cell fate specification have yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

TheTlxGene Regulates the Timing of Neurogenesis in the Cortex

Roy¹,

Kuznicki²,

Wu³

et al. 2004

J. Neurosci.

134

139

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The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a reduction in the size of the cerebral hemispheres and associated structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To determine whether the adult laminar phenotype has a developmental etiology and whether it is associated with a change in proliferation/differentiation decisions, we examined the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx Ϫ/Ϫ embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain.

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Section: Discussionmentioning

confidence: 99%

TheTlxGene Regulates the Timing of Neurogenesis in the Cortex

Roy¹,

Kuznicki²,

Wu³

et al. 2004

J. Neurosci.

134

139

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“…We examined and photographed the sections under confocal microscopy and counted BrdUlabeled and -unlabeled cells in the neuroepithelium on two histological sections (per level) at one rostral (anterior hypothalamic) and one caudal (MAM) level in three animals per age and genotype (wild type and Shhc). Then we calculated the labeling index (BrdU-labeled cells as percentage of total cells) (Takahashi et al, 1993;Warren et al, 1999;Ishibashi and McMahon, 2002).…”

Section: -Bromo-2ј-deoxyuridine Labelingmentioning

confidence: 99%

Role of NeuroepithelialSonic hedgehogin Hypothalamic Patterning

et al. 2009

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The hypothalamus is a region of the diencephalon with particularly complex patterning. Sonic hedgehog (Shh), encoding a protein with key developmental roles, shows a peculiar and dynamic diencephalic expression pattern. Here, we use transgenic strategies and in vitro experiments to test the hypothesis that Shh expressed in the diencephalic neuroepithelium (neural Shh) coordinates tissue growth and patterning in the hypothalamus. Our results show that neural Shh coordinates anteroposterior and dorsoventral patterning in the hypothalamus and in the diencephalon-telencephalon junction. Neural Shh also coordinates mediolateral hypothalamic patterning, since it is necessary for the lateral hypothalamus to attain proper size and is required for the specification of hypocretin/orexin cells. Finally, neural Shh is necessary to maintain expression of differentiation markers including survival factor Foxb1.

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“…Pax6 is expressed in radial glia of the developing cortex (Götz et al, 1998) and is indispensable for cortical neurogenesis from these cells (Warren et al, 1999;Heins et al, 2002). Moreover, Pax6 plays a crucial role in the generation of neurons from astroglial stem cells in the adult SEZ (Hack et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Functional Properties of Neurons Derived fromIn VitroReprogrammed Postnatal Astroglia

Berninger¹,

Costa²,

Koch³

et al. 2007

J. Neurosci.

331

289

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With the exception of astroglia-like cells in the neurogenic niches of the telencephalic subependymal or hippocampal subgranular zone, astroglia in all other regions of the adult mouse brain do not normally generate neurons. Previous studies have shown, however, that early postnatal cortical astroglia in culture can be reprogrammed to adopt a neuronal fate after forced expression of Pax6, a transcription factor (TF) required for proper neuronal specification during embryonic corticogenesis. Here we show that also the proneural genes neurogenin-2 and Mash1 (mammalian achaete schute homolog 1) possess the ability to reprogram astroglial cells from early postnatal cerebral cortex. By means of time-lapse imaging of green fluorescent astroglia, we provide direct evidence that it is indeed cells with astroglial characteristics that give rise to neurons. Using patch-clamp recordings in culture, we show that astroglia-derived neurons acquire active conductances and are capable of firing action potentials, thus displaying hallmarks of true neurons. However, independent of the TF used for reprogramming, astroglia-derived neurons appear to mature more slowly compared with embryonic-born neurons and fail to generate a functional presynaptic output within the culturing period. However, when cocultured with embryonic cortical neurons, astroglia-derived neurons receive synaptic input, demonstrating that they are competent of establishing a functional postsynaptic compartment. Our data demonstrate that single TFs are capable of inducing a remarkable functional reprogramming of astroglia toward a truly neuronal identity.

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The Transcription Factor, Pax6, is Required for Cell Proliferation and Differentiation in the Developing Cerebral Cortex

Cited by 155 publications

References 47 publications

TheTlxGene Regulates the Timing of Neurogenesis in the Cortex

TheTlxGene Regulates the Timing of Neurogenesis in the Cortex

Role of NeuroepithelialSonic hedgehogin Hypothalamic Patterning

Functional Properties of Neurons Derived fromIn VitroReprogrammed Postnatal Astroglia

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