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. 2008 Jul 8;105(27):9397-402.
doi: 10.1073/pnas.0802876105. Epub 2008 Jul 1.

Transcription Factor MEF2C Influences Neural Stem/Progenitor Cell Differentiation and Maturation in Vivo

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Free PMC article

Transcription Factor MEF2C Influences Neural Stem/Progenitor Cell Differentiation and Maturation in Vivo

Hao Li et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
At E18.5, in the absence of MEF2C, migrating neurons formed abnormal clusters above the subplate. Staining for committed neuronal markers Nestin and TuJ1 (TuJ1+) in the cortical plate (cp) is shown. Graph quantifies immunofluorescent markers in control versus Mef2c-nulls (*, P < 0.001; see Materials and Methods).
Fig. 2.
Fig. 2.
Severe E18.5 Mef2c-null phenotype shows altered organization in neocortex. (A) The immature neuronal marker DCX and mature neuronal marker NeuN were expressed by aberrantly clustered neurons in Mef2c-null neocortex. Arrowheads indicate the subplate. (B) Layer 5-specific marker Er81 and layer 6-specific marker Tbr1 were expressed by aberrantly clustered neurons in Mef2c-null neocortex. (C) GAD 65/67-positive mature interneurons clustered within the cortical plate; PSA-NCAM-positive proliferating neuronal progenitor cells showed a normal distribution in the Mef2c-null. (D) The morphology of radial glia labeled by BLBP was extremely aberrant in the severely affected phenotype of the Mef2c-null neocortex with a pattern similar to that of MAP-2-stained migrating neurons.
Fig. 3.
Fig. 3.
Mef2c-null mice at P7 and adult manifest a disorganized, more compacted cortical plate that lies abnormally close to the subplate. (A) NeuN and integrin α5 staining of neurons, labeled with BrdU upon their generation at E14.5, reveals the disorganized cortical plate in the null mice. (B) Layer 5 labeled with Er81 showed aberrant neuronal migration and little colocalization with Tbr1. (C) Similar to P7, in adult mice Nissl and Er81 staining reveal that Mef2c-null neocortex manifested a disorganized and compacted cortical plate, with layer 5 most affected. cp, cortical plate; sp, subplate. (Scale bars, 200 μm.)
Fig. 4.
Fig. 4.
Reduced excitability of Mef2c-null adult brain slices compared with control. (A) fEPSPs from hippocampal slices stimulated at the Schaeffer collateral afferent pathway and recorded in CA1 stratum radiatum. Responses of WT (ctrl) pyramidal neurons, as measured by initial slope, were significantly larger than those of Mef2c-null at 30% maximal stimulation intensity (n = 11; P < 0.05). (Inset Upper) Representative fEPSPs from hippocampal slice in MEA recordings. (Scale bar, 100 ms and 50 mV.) (Lower) Representative evoked EPSCs from layer 5 neocortex in whole-cell recordings at a holding potential of −70 mV (Scale bar, 50 ms and 100 pA.) (B) I/O curves of hippocampal fEPSP initial slope in response to increasing stimulation intensity. (C) Representative mEPSCs recorded from Mef2c-null and WT layer 5 pyramidal cells voltage clamped at −70 mV. Bar graphs show quantification of results. mEPSC frequency was decreased in Mef2c-null compared with WT cortical neurons (n = 33; *, P < 0.005), consistent with a decrease in synaptic release sites or probability of release.
Fig. 5.
Fig. 5.
Mef2c-null mice display altered anxiety-like behavior and decreased cognitive function. (A) The Elevated Plus Maze showed an apparent lowered state of anxiety without loss of function in mice lacking MEF2C compared with controls based on an increase in the percentage of time spent on the open arms but no difference in total arm entries, calculated over a 5-min period. (B) Locomotor activity was not different among null and control groups measured for 30 min as horizontal (locomotion) behavior. (C) Cued and contextual fear conditioning tests revealed that Mef2c-null mice manifest an altered anxiety phenotype, displaying freezing behavior in the altered context before tone onset [t(31) = 2.2, P < 0.05 by ANOVA; n ≥ 10 mice for each paradigm in A–F). Values are mean ± SEM. (D) Total number and order of arm entries on the Y maze were determined in a single 5-min test. (E) Novel object exploration was measured as contact time in one location for four 5-min trials and then a fifth trial with the object moved to a different spatial location. (F) For the paw-clasping observation, mice were suspended by their tails, observed for 10 s, and rated for clasping.

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