Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice

Goebbels, Sandra; Bormuth, Ingo; Bode, Ulli; Hermanson, Ola; Schwab, Markus H.; Nave, Klaus‐Armin

doi:10.1002/dvg.20256

Cited by 507 publications

(731 citation statements)

References 38 publications

(45 reference statements)

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“…eCB functions specifically underpinning pyramidal cell progenitor proliferation were elucidated in mice with conditional deletion of CB 1 Rs through Cre recombinase expressed under the control of regulatory sequences of NEX, a neuronal basic helix-loop-helix protein (15) (CB 1 R f/f,NEX-Cre ). Prominent Cre activity is observed by approximately E11.5 in cortical progenitors in NEX-Cre mice (15), ensuring the lack of CB 1 Rs in pyramidal cells at all developmental stages studied here. In these mutants (16), VZ/SVZ progenitor proliferation was significantly impaired, as indicated by reduced Ki67 and GOLGA5 cell density in proliferative zones ( Fig.…”

Section: Cb1r Expression In Developingmentioning

confidence: 52%

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Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning

Mulder

Aguado²,

Keimpema³

et al. 2008

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

279

356

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Endocannabinoids (eCBs) have recently been identified as axon guidance cues shaping the connectivity of local GABAergic interneurons in the developing cerebrum. However, eCB functions during pyramidal cell specification and establishment of longrange axonal connections are unknown. Here, we show that eCB signaling is operational in subcortical proliferative zones from embryonic day 12 in the mouse telencephalon and controls the proliferation of pyramidal cell progenitors and radial migration of immature pyramidal cells. When layer patterning is accomplished, developing pyramidal cells rely on eCB signaling to initiate the elongation and fasciculation of their long-range axons. Accordingly, CB 1 cannabinoid receptor (CB1R) null and pyramidal cellspecific conditional mutant (CB 1R f/f,NEX-Cre ) mice develop deficits in neuronal progenitor proliferation and axon fasciculation. Likewise, axonal pathfinding becomes impaired after in utero pharmacological blockade of CB 1Rs. Overall, eCBs are fundamental developmental cues controlling pyramidal cell development during corticogenesis.excitation ͉ glutamate ͉ layer patterning ͉ neocortex ͉ neurogenesis P yramidal cell specification follows a sequential scenario in the developing cerebrum: commitment of progenitor cells to the neuronal lineage occurs in the subcortical proliferative ventricular zone (VZ) and subventricular zone (SVZ). Immature pyramidal cells undergo radial migration to populate the cortical plate (CP) (1), where they acquire layer-specific neurochemical and morphological diversity (2). Pyramidal cell positioning and patterning of their corticofugal and intracortical axons is in part achieved via transcriptional control acting throughout cellular identification (2). However, epigenetic microenvironmental cues, provided by neural progenitors, radial glia, and immature neurons, are also fundamental in attaining cortical cell identity with particularly robust effects on pathfinding and directional growth of long-range axons (3).Endocannabinoids [eCBs; anandamide (AEA) and 2-arachidonoylglycerol] control various forms of synaptic plasticity at cortical glutamatergic synapses in the postnatal brain (4) through functional CB 1 cannabinoid receptors (CB 1 Rs) (5). During brain development, eCBs control neuronal fate decision (6), interneuron migration (7), and axonal specification (8). Developmental eCB actions are underpinned by a temporally defined assembly of functional eCB signaling networks with coincident expression of sn-1-diacylglycerol lipases (DAGL␣/␤) (9) and N-arachidonoyl-phosphatidyl ethanolamine (NAPE)-selective phospholipase D involved in eCB synthesis, fatty-acid amide hydrolase (FAAH) (an enzyme preferentially degrading AEA), and CB 1 Rs (8). The selective axonal targeting of CB 1 Rs and DAGLs in immature neurons suggests that eCBs may function in either cell-autonomous (6, 9) or target-derived (8) manner to control axonal elongation and postsynaptic target selection, respectively.Although recent findings in both mammals (8) and nonmammalian v...

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Section: Cb1r Expression In Developingmentioning

confidence: 52%

“…We assessed the in vivo significance of our findings in CB 1 R f/f,NEX-Cre mice (15). In new-born CB 1 R f/f,NEX-Cre (Fig.…”

Section: Cb1r Deletion Reveals Fasciculation Deficitsmentioning

confidence: 97%

Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning

Mulder

Aguado²,

Keimpema³

et al. 2008

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

279

356

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“…This result suggests that competition may play a role, but because global NR1 knockouts have severely compromised viability (they have reduced body weight, and none survive pass weaning) we cannot rule out compensatory effects. Additionally, the NEX promoter drives CRE expression as early as E11.5 (17), as compared with the postnatal viral infection, which could also account for the differences. Future work, perhaps with specific inducible CRE lines of mice (16), should be able to carefully separate the cell-autonomous role of NMDA receptor function from any part it has in comparing the afferent activity of competing axons.…”

Section: Resultsmentioning

confidence: 99%

NMDA receptors inhibit synapse unsilencing during brain development

Adesnik

Li²,

During³

et al. 2008

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

143

130

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How the billions of synapses in the adult mammalian brain are precisely specified remains one of the fundamental questions of neuroscience. Although a genetic program is likely to encode the basic neural blueprint, much evidence suggests that experiencedriven activity through NMDA receptors wires up neuronal circuits by inducing a process similar to long-term potentiation. To test this notion directly, we eliminated NMDA receptors before and during synaptogenesis in single cells in vitro and in vivo. Although the prevailing model would predict that NMDA receptor deletion should strongly inhibit the maturation of excitatory circuits, we find that genetic ablation of NMDA receptor function profoundly increases the number of functional synapses between neurons. Conversely, reintroduction of NMDA receptors into NR1-deficient neurons reduces the number of functional inputs, a process requiring network activity and NMDA receptor function. Although NMDA receptor deletion increases the strength of unitary connections, it does not alter neuronal morphology, suggesting that basal NMDA receptor activation blocks the recruitment of AMPA receptors to silent synapses. Based on these results we suggest a new model for the maturation of excitatory synapses in which ongoing activation of NMDA receptors prevents premature synaptic maturation by ensuring that only punctuated bursts of activity lead to the induction of a functional synapse for the activity-dependent wiring of neural circuitry.AMPA receptor ͉ long-term potentiation C onsiderable evidence links NMDA receptor activation to the maturation of excitatory circuitry during brain development (1-3). Most studies, however, have relied on widespread pharmacological inhibition or broad genetic deletion of NMDA receptors to explore their involvement in synaptic development (4-8). To avoid indirect effects that such manipulations might have by generally altering network activity (9-11), we abolished NMDA receptor protein expression in sparsely distributed cells in the hippocampus by introduction of CRE recombinase to neurons in a floxed NR1 mouse (NR1 fl/fl ) (12). Mosaic deletion permitted simultaneous paired whole-cell recordings from CRE-expressing and untransfected neighboring cells to provide a rigorous, quantitative, and internally controlled comparison of the physiological effects of NR1 deletion. ResultsFirst, we biolistically transfected a plasmid encoding CRE recombinase into cells in organotypic hippocampal slice cultures from NR1 fl/fl mice. The low efficacy of this transfection technique leads to NR1 deletion in only a few cells in the slice. A GFP reporter in the construct identified CRE-expressing cells. Two weeks after transfection, synaptic NMDA currents were strongly reduced in GFP ϩ neurons but not in their untransfected neighbors (Fig. 1a, I transfected /I control ϭ 0.23 Ϯ 0.03, n ϭ 41 pairs, P Ͻ 10 Ϫ11 ). As a control, transfection of CRE on its own into wild-type slices did not significantly affect NMDA or AMPA receptor-mediated synaptic currents [NMDA: I t...

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“…To separate Sip1's function in early cortical progenitor cells from its role in postmitotic neurons, we used a Nex-cre approach. Previous studies have found that the majority of cells that produce Cre driven by the Nex promoter are nondividing neurons, whereas only a very small fraction are proliferative 16,20 . Moreover, immunostaining of Nex-driven Cre and neuronal HuC/D in the neocortex showed an almost complete overlay of both at E14.5 ( Supplementary Fig.…”

Section: Sip1 Levels Are High In Postmitotic Neocortical Cellsmentioning

confidence: 99%

“…To investigate the function(s) of Sip1 in the developing neocortex (beginning at E11.5), we analyzed loxP/Cre-based conditional knockout mice. We deleted Sip1 in either the entire mouse CNS (using a Nestin-cre approach), dorsal telencephalic precursors (Emx1-cre) or dorsal telencephalic postmitotic cells (Nex-cre) [15][16][17] . We found that specific ablation of Sip1 in the neocortex led to a temporal shift in corticogenesis, mediated by premature feedback signaling from cortical plate neurons to progenitor cells via Ntf3 and Fgf9.…”

mentioning

confidence: 99%

Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

et al. 2009

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The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non-cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and increased generation of glial precursors, and enhanced postnatal astrocytogenesis. The premature upper-layer generation coincided with overexpression of the neurotrophin-3 (Ntf3) gene and upregulation of fibroblast growth factor 9 (Fgf9) gene expression preceded precocious gliogenesis. Exogenous application of Fgf9 to mouse cortical slices induced excessive generation of glial precursors in the germinal zone. Our data suggest that Sip1 restrains the production of signaling factors in postmitotic neurons that feed back to progenitors to regulate the timing of cell fate switch and the number of neurons and glial cells throughout corticogenesis.

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Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice

Cited by 507 publications

References 38 publications

Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning

Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning

NMDA receptors inhibit synapse unsilencing during brain development

Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

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