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The generation of superficial cortical layers is regulated by levels of the transcription factor Pax6.

ABSTRACT: The ventricular zone (VZ) of the embryonic dorsal telencephalon is a major site for generating cortical projection neurons. The transcription factor Pax6 is highly expressed in apical progenitors (APs) residing in the VZ from the earliest stages of corticogenesis. Previous studies mainly focused on Pax6(-/-) mice have implicated Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of superficial cortical layers. We analyzed the developing cortex of PAX77 transgenic mice that overexpress Pax6 in its normal domains of expression. We show that Pax6 overexpression increases cell cycle length of APs and drives the system toward neurogenesis. These effects are specific to late stages of corticogenesis, when superficial layer neurons are normally generated, in cortical regions that express Pax6 at the highest levels. The number of superficial layer neurons is reduced in postnatal PAX77 mice, whereas radial migration and lamina specification of cortical neurons are not affected by Pax6 overexpression. Conditional deletion of Pax6 in cortical progenitors at midstages of corticogenesis, by using a tamoxifen-inducible Emx1-CreER line, affected both numbers and specification of late-born neurons in superficial layers of the mutant cortex. Our analyses suggest that correct levels of Pax6 are essential for normal production of superficial layers of the cortex.

SUBMITTER: Georgala PA

PROVIDER: S-EPMC3000564 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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The generation of superficial cortical layers is regulated by levels of the transcription factor Pax6.

Georgala Petrina A PA Manuel Martine M Price David J DJ

Cerebral cortex (New York, N.Y. : 1991) 20100422 1

The ventricular zone (VZ) of the embryonic dorsal telencephalon is a major site for generating cortical projection neurons. The transcription factor Pax6 is highly expressed in apical progenitors (APs) residing in the VZ from the earliest stages of corticogenesis. Previous studies mainly focused on Pax6(-/-) mice have implicated Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of superficial cortical layers. We analyzed the developing cortex of PAX77 transgenic m ...[more]

PMID: 20413449

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Project description:BackgroundWe studied whether regulation of Cdca7 (Cell division cycle associated 7) expression by transcription factor Pax6 contributes to Pax6's cellular actions during corticogenesis. The function of Cdca7 in mediating Pax6's effects during corticogenesis has not been explored. Pax6 is expressed by radial glial progenitors in the ventricular zone of the embryonic cortical neuroepithelium, where it is required for the development of a normal complement of Tbr2-expressing intermediate progenitor cells in the subventricular zone. Pax6's expression levels are graded across the ventricular zone, with highest levels laterally where Tbr2-expressing progenitors are generated in greatest numbers at early stages of corticogenesis.MethodsWe used in situ hybridization and immunohistochemistry to analyse patterns of Cdca7 and Pax6 expression in cortical tissue from wild-type and Pax6 -/- embryos. In each genotype we compared the graded expression of the two genes quantitatively at several ages. To test whether defects in Cdca7 expression in lateral cortical cells might contribute to the cellular defects in this region caused by Pax6 loss, we electroporated a Cdca7 expression vector into wild-type lateral cortex and examined the effect on the production of Tbr2-expressing cells.ResultsWe found that Cdca7 is co-expressed with Pax6 in cortical progenitors, at levels opposite to those of Pax6. Lowest levels of Cdca7 are found in the radial glial progenitors of lateral cortex, where Pax6 levels are highest. Higher levels of Cdca7 are found in ventral telencephalon, where Pax6 levels are low. Loss of Pax6 causes Cdca7 expression to increase in the lateral cortex. Elevating Cdca7 in normal lateral cortical progenitors to levels close to those normally found in ventral telencephalon reduces their production of Tbr2-expressing cells early in lateral cortical formation.ConclusionOur results suggest that Pax6 normally represses Cdca7 expression in the lateral cortex and that repression of Cdca7 in cells of this region is required for their production of a normal complement of Tbr2-expressing intermediate progenitors.

Project description:BackgroundCortical electrical stimulation (CES) techniques are practical tools in neurorehabilitation that are currently being used to test models of functional recovery after neurologic injury. However, the mechanisms by which CES has therapeutic effects, are not fully understood.ObjectiveIn this study, we investigated the effects of CES on unit activity of different neuronal elements in layers of rat primary motor cortex after the offset of stimulation. We evaluated the effects of monopolar CES pulse polarity (anodic-first versus cathodic-first) using various stimulation frequencies and amplitudes on unit activity after stimulation.MethodsA penetrating single shank silicon microelectrode array enabled us to span the entirety of six layer motor cortex allowing simultaneous electrophysiologic recordings from different depths after monopolar CES. Neural spiking activity before the onset and after the offset of CES was modeled using point processes fit to capture neural spiking dynamics as a function of extrinsic stimuli based on generalized linear model methods.ResultsWe found that neurons in lower layers have a higher probability of being excited after anodic CES. Conversely, neurons located in upper cortical layers have a higher probability of being excited after cathodic stimulation. The opposing effects observed following anodic versus cathodic stimulation in upper and lower layers were frequency- and amplitude-dependent.ConclusionsThe data demonstrates that the poststimulus changes in neural activity after manipulation of CES parameters changes according to the location (depth) of the recorded units in rat primary motor cortex. The most effective pulse polarity for eliciting action potentials after stimulation in lower layers was not as effective in upper layers. Likewise, lower amplitudes and frequencies of CES were more effective than higher amplitudes and frequencies for eliciting action potentials. These results have important implications in the context of maximizing efficacy of CES for neurorehabilitation and neuroprosthetic applications.

Project description:Background and Purpose- We investigated cortical superficial siderosis (cSS) progression and its clinical relevance for incident lobar intracerebral hemorrhage (ICH) risk, in probable cerebral amyloid angiopathy presenting with neurological symptoms and without ICH at baseline. Methods- Consecutive patients meeting modified Boston criteria for probable cerebral amyloid angiopathy from a single-center cohort who underwent magnetic resonance imaging (MRI) at baseline and during follow-up were analyzed. cSS progression was assessed by comparison of the baseline and follow-up images. Patients were followed prospectively for incident symptomatic ICH. cSS progression and first-ever ICH risk were investigated in Cox proportional hazard models adjusting for confounders. Results- The cohort included 118 probable cerebral amyloid angiopathy patients: 72 (61%) presented with transient focal neurological episodes and 46 (39%) with cognitive complaints prompting the baseline MRI investigation. Fifty-two patients (44.1%) had cSS at baseline. During a median scan interval of 2.2 years (interquartile range, 1.2-4.4 years) between the baseline (ie, first) MRI and the latest MRI, cSS progression was detected in 33 (28%) patients. In multivariable logistic regression, baseline cSS presence (odds ratio, 4.04; 95% CI, 1.53-10.70; P=0.005), especially disseminated cSS (odds ratio, 9.12; 95% CI, 2.85-29.18; P<0.0001) and appearance of new lobar microbleeds (odds ratio, 4.24; 95% CI, 1.29-13.9; P=0.017) were independent predictors of cSS progression. For patients without an ICH during the interscan interval (n=105) and subsequent follow-up (median postfinal MRI time, 1.34; interquartile range, 0.3-3 years), cSS progression independently predicted increased symptomatic ICH risk (hazard ratio, 3.76; 95% CI, 1.37-10.35; P=0.010). Conclusions- Our results suggest that cSS evolution may be a useful biomarker for assessing disease progression and ICH risk in cerebral amyloid angiopathy patients and a candidate biomarker for clinical studies and trials.

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The generation of superficial cortical layers is regulated by levels of the transcription factor Pax6.

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The generation of superficial cortical layers is regulated by levels of the transcription factor Pax6.

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