Biomedical subjects

Inma Cobos

Publications and source records attributed to Inma Cobos.

6 recordsLinked to original sources

PubMed2006

Severe hearing loss in Dlxl mutant mice.

The Dlx homeobox gene family participates in regulating middle and inner ear development. A significant role for Dlxl, in particular,has been demonstrated in the development of the middle ear ossicles, but the functional consequences of Dlx.l gene mutation on hearing thresholds has not been assessed. The present study characterizes auditory brainstem responses to click and tonal stimuli in a non-lethal variant of a Dlxl gene knockout. We found that peripheral hearing thresholds for click and tonal stimuli were significantly elevated in homozygous Dlxl knockout (Dlxl-/ ) compared to both heterozygous (Dlxl+/ ) and wild type (Dlxl+/+) mice. Thus, abnormal mor-phogenesis of the incus and stapes that has been documented previously with histological measures is now known to result in a severe peripheral hearing deficit.

Animals↗

PubMed2006

Cellular patterns of transcription factor expression in developing cortical interneurons.

Most gamma-aminobutyric acidergic interneurons in the neocortex and hippocampus are derived from subpallial progenitors in the medial ganglionic eminence and migrate tangentially to the pallium, where they differentiate into a diverse set of neuronal subtypes. Toward elucidating the mechanisms underlying the generation of interneuron diversity, we have studied in mice the expression patterns in differentiating and mature neocortical interneurons of 8 transcription factors, including 6 homeobox (Dlx1, Dlx2, Dlx5, Arx, Lhx6, Cux2), 1 basic helix-loop-helix, (NPAS1), and 1 bZIP (MafB). Their patterns of expression change during interneuron differentiation and show distinct distributions within interneuron subpopulations in adult neocortex. This study is a first step to define the combinatorial codes of transcription factors that participate in regulating the specification and function of cortical interneuron subtypes.

Aging↗

PubMed2005

Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy.

Dlx homeodomain transcription factors are essential during embryonic development for the production of forebrain GABAergic interneurons. Here we show that Dlx1 is also required for regulating the functional longevity of cortical and hippocampal interneurons in the adult brain. We demonstrate preferential Dlx1 expression in a subset of cortical and hippocampal interneurons which, in postnatal Dlx1 mutants, show a time-dependent reduction in number. This reduction preferentially affects calretinin(+) (bipolar cells) and somatostatin(+) subtypes (for example, bitufted cells), whereas parvalbumin(+) subpopulations (basket cells and chandelier cells) seem to be unaffected. Cell transplantation analysis demonstrates that interneuron loss reflects cell-autonomous functions of Dlx1. The decrease in the number of interneurons was associated with a reduction of GABA-mediated inhibitory postsynaptic current in neocortex and hippocampus in vitro and cortical dysrhythmia in vivo. Dlx1 mutant mice show generalized electrographic seizures and histological evidence of seizure-induced reorganization, linking the Dlx1 mutation to delayed-onset epilepsy associated with interneuron loss.

Aging↗

PubMed2005

The vertebrate ortholog of Aristaless is regulated by Dlx genes in the developing forebrain.

The Dlx transcription factors have a central role in controlling the development of gamma-aminobutyric acid (GABA)-ergic neurons in the forebrain. However, little is known about how they control the properties of GABAergic neurons. One candidate is the Aristaless (Arx) homeobox gene, which lies genetically downstream of the fly Dlx gene (Distal-less, Dll). The expression of Arx in the mouse forebrain includes Dlx-expressing territories, such us the ventral thalamus, parts of the hypothalamus, and the ganglionic eminences and their derivatives in the subpallial telencephalon, and is expressed, as with the Dlx genes, in cortical GABAergic neurons. By using gain-of-function and loss-of-function assays in mouse and chicken embryos, we show that the Dlx genes have a conserved role in regulating the expression of Arx in the forebrain of vertebrates. Ectopic expression of Dlx genes with electroporation in brain slices from mouse embryos and in the neural tube of chick embryos shows that Dlx genes are sufficient to induce Arx ectopically. Moreover, we provide evidence that the Dlx genes exert a functionally relevant role in regulating Arx in vivo, as shown by the severe reduction in the expression of Arx in Dlx1/2 double-knockout mice. Therefore, our results suggest evolutionarily conserved functions of Dlx genes in regulating Arx expression between Drosophila and vertebrates.

Animals↗

PubMed2004

Origins of cortical interneuron subtypes.

Cerebral cortical functions are conducted by two general classes of neurons: glutamatergic projection neurons and GABAergic interneurons. Distinct interneuron subtypes serve distinct roles in modulating cortical activity and can be differentially affected in cortical diseases, but little is known about the mechanisms for generating their diversity. Recent evidence suggests that many cortical interneurons originate within the subcortical telencephalon and then migrate tangentially into the overlying cortex. To test the hypothesis that distinct interneuron subtypes are derived from distinct telencephalic subdivisions, we have used an in vitro assay to assess the developmental potential of subregions of the telencephalic proliferative zone (PZ) to give rise to neurochemically defined interneuron subgroups. PZ cells from GFP+ donor mouse embryos were transplanted onto neonatal cortical feeder cells and assessed for their ability to generate specific interneuron subtypes. Our results suggest that the parvalbumin- and the somatostatin-expressing interneuron subgroups originate primarily within the medial ganglionic eminence (MGE) of the subcortical telencephalon, whereas the calretinin-expressing interneurons appear to derive mainly from the caudal ganglionic eminence (CGE). These results are supported by findings from primary cultures of cortex from Nkx2.1 mutants, in which normal MGE fails to form but in which the CGE is less affected. In these cultures, parvalbumin- and somatostatin-expressing cells are absent, although calretinin-expressing interneurons are present. Interestingly, calretinin-expressing bipolar interneurons were nearly absent from cortical cultures of Dlx1/2 mutants. By establishing spatial differences in the origins of interneuron subtypes, these studies lay the groundwork for elucidating the molecular bases for their distinct differentiation pathways.

Animals↗

PubMed2003

Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4.

One line of mice harboring a cardiac-specific epoxygenase transgene developed head swelling and rapid neurological decline in young adulthood, and had marked hydrocephalus of the lateral and third ventricles. The transgene was found to be inserted into an intron in the mouse Rfx4 locus. This insertion apparently prevented expression of a novel variant transcript of RFX4 (RFX4_v3), a member of the regulatory factor X family of winged helix transcription factors. Interruption of two alleles resulted in profound failure of dorsal midline brain structure formation and perinatal death, presumably by interfering with expression of downstream genes. Interruption of a single allele prevented formation of the subcommissural organ, a structure important for cerebrospinal fluid flow through the aqueduct of Sylvius, and resulted in congenital hydrocephalus. These data implicate the RFX4_v3 variant transcript as being crucial for early brain development, as well as for the genesis of the subcommissural organ. These findings may be relevant to human congenital hydrocephalus, a birth defect that affects approximately 0.6 per 1000 newborns.

Alternative Splicing↗