Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons

Potter, Gregory B.; Petryniak, Magdalena A.; Shevchenko, Eugenia; McKinsey, Gabriel L.; Ekker, Marc; Rubenstein, John L.R.

doi:10.1016/j.mcn.2008.10.003

Cited by 103 publications

(121 citation statements)

References 78 publications

(138 reference statements)

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“…Dlx genes have been to shown to positively auto-regulate their transcription level by binding to their own enhancers such as I12b both in vivo and in vitro (Zerucha et al, 2000;Poitras et al, 2007;Potter et al, 2009). Given the upregulation of E2F7 in the Rb mutant brain, we sought to determine whether E2F7 upregulation itself can repress the enhancer activity of I12b and/or the endogenous activities of the Dlx1 and Dlx2 promoters.…”

Section: Repressor E2fs Such As E2f7 Negatively Regulate Dlx1/dlx2 Gementioning

confidence: 99%

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Ghanem¹,

Andrusiak²,

Svoboda³

et al. 2012

Journal of Neuroscience

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During brain morphogenesis, the mechanisms through which the cell cycle machinery integrates with differentiation signals remain elusive. Here we show that the Rb/E2F pathway regulates key aspects of differentiation and migration through direct control of the Dlx1 and Dlx2 homeodomain proteins, required for interneuron specification. Rb deficiency results in a dramatic reduction of Dlx1 and Dlx2 gene expression manifested by loss of interneuron subtypes and severe migration defects in the mouse brain. The Rb/E2F pathway modulates Dlx1/Dlx2 regulation through direct interaction with a Dlx forebrain-specific enhancer, I12b, and the Dlx1/Dlx2 proximal promoter regions, through repressor E2F sites both in vitro and in vivo. In the absence of Rb, we demonstrate that repressor E2Fs inhibit Dlx transcription at the Dlx1/Dlx2 promoters and Dlx1/2-I12b enhancer to suppress differentiation. Our findings support a model whereby the cell cycle machinery not only controls cell division but also modulates neuronal differentiation and migration through direct regulation of the Dlx1/Dlx2 bigene cluster during embryonic development.

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Section: Repressor E2fs Such As E2f7 Negatively Regulate Dlx1/dlx2 Gementioning

confidence: 99%

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Ghanem¹,

Andrusiak²,

Svoboda³

et al. 2012

Journal of Neuroscience

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“…Deletion of one of these genes, Dlx1, in mice leads to selective interneuron loss and seizures (22). In the Dlx1/2-I12b-Cre transgenic mouse, an intergenic Dlx1 and Dlx2 enhancer drives expression of Cre recombinase specifically in GABAergic neurons in the forebrain (23). We have used this Dlx-Cre mouse line in conjunction with a floxed Na V 1.1 mouse line to directly test the hypothesis that deletion of Na V 1.1 channels in the forebrain is sufficient to recapitulate the premature death and seizure phenotypes observed in the Na V 1.1-deletion model of DS.…”

mentioning

confidence: 99%

Specific deletion of Na _V 1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

Cheah¹,

Westenbroek³

et al. 2012

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

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Heterozygous loss-of-function mutations in the brain sodium channel Na V 1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis that impaired excitability of GABAergic inhibitory neurons is the cause of epilepsy and premature death in DS. However, other classes of GABAergic interneurons are less impaired, so the direct cause of hyperexcitability, epilepsy, and premature death has remained unresolved. We generated a floxed Scn1a mouse line and used the Cre-Lox method driven by an enhancer from the Dlx1,2 locus for conditional deletion of Scn1a in forebrain GABAergic neurons. Immunocytochemical studies demonstrated selective loss of Na V 1.1 channels in GABAergic interneurons in cerebral cortex and hippocampus. Mice with this deletion died prematurely following generalized tonic-clonic seizures, and they were equally susceptible to thermal induction of seizures as mice with global deletion of Scn1a. Evidently, loss of Na V 1.1 channels in forebrain GABAergic neurons is both necessary and sufficient to cause epilepsy and premature death in DS.V oltage gated sodium (Na V ) channels are composed of a 260-kDa pore-forming α subunit and one or more smaller auxiliary β subunits (1, 2). The Na V 1.1, Na V 1.2, Na V 1.3, and Na V 1.6 isoforms are highly expressed in the brain, where they initiate and propagate action potentials in neurons. Na V 1.1 and Na V 1.3 are prominently expressed in the cell soma and axon initial segment where they integrate incoming information from the dendrites, whereas Na V 1.2 channels are found in unmyelinated axons and dendrites, and Na V

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“…To circumvent this issue, we developed a conditional deletion of Dlx1 restricted to forebrain GABAergic neurons using a floxed conditional allele of Dlx1 and DlxI12b-Cre (I12b-Cre). DlxI12b is an enhancer element of Dlx1 (40,41). By placing Cre-recombinase under the control of this enhancer, which is not expressed in the primordia of the middle ear, recombination occurs in 95% of cortical interneurons (41).…”

mentioning

confidence: 99%

“…DlxI12b is an enhancer element of Dlx1 (40,41). By placing Cre-recombinase under the control of this enhancer, which is not expressed in the primordia of the middle ear, recombination occurs in 95% of cortical interneurons (41). We will refer to these Dlx1 −/f ;I12b-Cre animals as conditional knockout animals (cKO) and heterozygous littermates (Dlx1 +/f ;I12b-Cre) as controls (CT).…”

mentioning

confidence: 99%

Chronic reduction in inhibition reduces receptive field size in mouse auditory cortex

Seybold

Stanco

Cho³

et al. 2012

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

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Inhibitory interneurons regulate the responses of cortical circuits. In auditory cortical areas, inhibition from these neurons narrows spectral tuning and shapes response dynamics. Acute disruptions of inhibition expand spectral receptive fields. However, the effects of long-term perturbations of inhibitory circuitry on auditory cortical responses are unknown. We ablated ∼30% of dendrite-targeting cortical inhibitory interneurons after the critical period by studying mice with a conditional deletion of Dlx1. Following the loss of interneurons, baseline firing rates rose and tone-evoked responses became less sparse in auditory cortex. However, contrary to acute blockades of inhibition, the sizes of spectral receptive fields were reduced, demonstrating both higher thresholds and narrower bandwidths. Furthermore, long-latency responses at the edge of the receptive field were absent. On the basis of changes in response dynamics, the mechanism for the reduction in receptive field size appears to be a compensatory loss of corticocortically (CC) driven responses. Our findings suggest chronic conditions that feature changes in inhibitory circuitry are not likely to be well modeled by acute network manipulations, and compensation may be a critical component of chronic neuronal conditions. P rocessing of auditory information in the auditory cortex underlies the conscious perception of sound and speech comprehension. Inhibitory interneurons, representing ∼20% of cortical neurons (1), regulate this processing by shaping the spectral tuning (2-13), temporal tuning (14-16), and response dynamics of local excitatory neurons (5-11). Inhibitory interneurons form multiple subtypes on the basis of morphology, physiology, and biochemistry (1, 17) that likely serve distinct roles in cortical processing.Loss of inhibitory interneurons is observed in conditions that affect cortical processing in humans, and in animal models of human disorders, including aging (18, 19), autism (20), schizophrenia (21-23), traumatic brain injury (TBI) (24), hearing loss (25-28), and tinnitus (29). Often, a particular disease is associated with a specific deficit in a subset of interneurons. For example, rodent models of autism demonstrate a loss of parvalbumin positive (PV + ) interneurons (20), whereas aging and TBI models show a greater loss of somatostatin (SST) + interneurons than other interneuron populations (19,24). The disruption of specific interneuron populations may underlie the particular cognitive defects associated with each condition. Therefore, it is necessary to understand the effects following chronic reductions of particular interneuron subtypes.One mouse model of an adult-onset loss of dendrite-targeting interneurons (DTIs) is the Dlx1 mutant (30). Dlx1 encodes a homeobox transcription factor from the Dlx family that regulates the development, migration, and survival of cortical interneurons (30-32). In Dlx1 mutants, the other Dlx family members compensate for the deficiency and thereby allow interneurons to migrate into cortex (30)....

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Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons

Cited by 103 publications

References 78 publications

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Specific deletion of Na _V 1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

Chronic reduction in inhibition reduces receptive field size in mouse auditory cortex

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Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons

Cited by 103 publications

References 78 publications

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Specific deletion of Na V 1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

Chronic reduction in inhibition reduces receptive field size in mouse auditory cortex

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Specific deletion of Na _V 1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome