Cellular patterns of transcription factor expression in developing cortical interneurons

Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California at San Francisco, San Francisco, CA 94158-2611, USA.
Cerebral Cortex (Impact Factor: 8.67). 08/2006; 16 Suppl 1(Suppl. 1):i82-8. DOI: 10.1093/cercor/bhk003
Source: PubMed

ABSTRACT 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.

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    • "PV+ interneurons are born at approximately E12.5 to E15.5 in the medial ganglionic eminence of the ventral telencephalon, and migrate tangentially to the dorsal cortex where they integrate into the cortical circuitry [32]–[38]. The migration and integration of cortical interneurons is ongoing at the time of birth, as is the maturation of interneuron identity [32]. "
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    ABSTRACT: Fibroblast growth factors (Fgfs) and their receptors (Fgfr) are expressed in the developing and adult CNS. Previous studies demonstrated a decrease in cortical interneurons and locomotor hyperactivity in mice with a conditional Fgfr1 deletion generated in radial glial cells during midneurogenesis (Fgfr1 f/f ;hGfapCre+). Here, we report earlier and more extensive inactivation of Fgfr1 in neuroepithelial cells of the CNS (Fgfr1 f/f ;NesCre+). Similar to findings in Fgfr1 f/f ;hGfapCre+ mice, parvalbumin positive (PV+) cortical interneurons are also decreased in the neocortex of Fgfr1f/f;NesCre+ mice when compared to control littermates (Fgfr1f/f). Fgfr1f/f;NesCre+ embryos do not differ from controls in the initial specification of GABAergic cells in the ganglionic eminence (GE) as assessed by in situ hybridization for Dlx2, Mash1 and Nkx2. Equal numbers of GABAergic neuron precursors genetically labeled with green fluorescent protein (GFP) were observed at P0 in Fgfr1 f/f ;hGfapCre+;Gad1-GFP mutant mice. However, fewer GFP+ and GFP+/PV+ interneurons were observed in these mutants at adulthood, indicating that a decrease in cortical interneuron markers is occurring postnatally. Fgfr1 is expressed in cortical astrocytes in the postnatal brain. To test whether the astrocytes of mice lacking Fgfr1 are less capable of supporting interneurons, we co-cultured wild type Gad1-GFP+ interneuron precursors isolated from the medial GE (MGE) with astrocytes from Fgfr1f/f control or Fgfr1 f/f ;hGfapCre+ mice. Interneurons grown on Fgfr1 deficient astrocytes had small soma size and fewer neurites per cell, but no differences in cell survival. Decreased soma size of Gad67 immunopositive interneurons was also observed in the cortex of adult Fgfr1 f/f ;NesCre+ mice. Our data indicate that astrocytes from Fgfr1 mutants are impaired in supporting the maturation of cortical GABAergic neurons in the postnatal period. This model may elucidate potential mechanisms of impaired PV interneuron maturation relevant to neuropsychiatric disorders that develop in childhood and adolescence. Citation: Smith KM, Maragnoli ME, Phull PM, Tran KM, Choubey L, et al. (2014) Fgfr1 Inactivation in the Mouse Telencephalon Results in Impaired Maturation of Interneurons Expressing Parvalbumin. PLoS ONE 9(8): e103696. doi:10.1371/journal.pone.0103696
    PLoS ONE 08/2014; 9(8). DOI:10.1371/journal.pone.0103696 · 3.23 Impact Factor
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    • "Importantly, we further investigated if the vulnerability of E14 versus E17 neurons in culture was similar to that of homogenized cortical tissues from E14 versus E17 embryos and from in vitro separated deep versus superficial layers of young and aged adult mice. Cux2, well known for its preferential expression in superficial cortical layers (Belgard et al., 2011; Cobos et al., 2006; Gingras et al., 2005), was used as a control for correct laminar separation and the postsynaptic marker PSD-95 to detect synaptic alterations (Leuba et al., 2008a, 2008b). Thus, these experiments were designed for reproducing the differential vulnerability of cortical layers in vitro leading to a better understanding of this phenomenon in aging and AD. 2. Methods 2.1. "
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    ABSTRACT: Superficial layers I to III of the human cerebral cortex are more vulnerable toward Aβ peptides than deep layers V to VI in aging. Three models of layers were used to investigate this pattern of frailty. First, primary neurons from E14 and E17 embryonic murine cortices, corresponding respectively to future deep and superficial layers, were treated either with Aβ1-42, okadaic acid, or kainic acid. Second, whole E14 and E17 embryonic cortices, and third, in vitro separated deep and superficial layers of young and old C57BL/6J mice, were treated identically. We observed that E14 and E17 neurons in culture were prone to death after the Aβ and particularly the kainic acid treatment. This was also the case for the superficial layers of the aged cortex, but not for the embryonic, the young cortex, and the deep layers of the aged cortex. Thus, the aged superficial layers appeared to be preferentially vulnerable against Aβ and kainic acid. This pattern of vulnerability corresponds to enhanced accumulation of senile plaques in the superficial cortical layers with aging and Alzheimer's disease.
    Neurobiology of aging 09/2013; 35(2). DOI:10.1016/j.neurobiolaging.2013.08.005 · 5.01 Impact Factor
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    • "Since previous studies had been successful in expanding neural stem cells in serum-free or serum-containing media with the addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF, or FGF-2) [41], [42], we tested these different protocols for MGE cells. We used MGE cells dissociated from E12.5/E13.5 transgenic embryos that expressed β-Galactosidase (β-Gal) or GFP in postmitotic MGE neurons, including immature cortical interneurons, under the control of a zebrafish Dlx5/6 enhancer or a mouse Lhx6-GFP BAC transgene [43], [44], [45]. Prolonged MGE culture (more than 10 days in vitro), or passage of cells that involved trypsinization, resulted in a marked decrease in Nkx2-1 (data not shown) and Lhx6-GFP expression (See Text T1, Methods M1, M2 and Figure S1 in File S1). "
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    ABSTRACT: The medial ganglionic eminence (MGE) is an embryonic forebrain structure that generates the majority of cortical interneurons. MGE transplantation into specific regions of the postnatal central nervous system modifies circuit function and improves deficits in mouse models of epilepsy, Parkinson's disease, pain, and phencyclidine-induced cognitive deficits. Herein, we describe approaches to generate MGE-like progenitor cells from mouse embryonic stem (ES) cells. Using a modified embryoid body method, we provided gene expression evidence that mouse ES-derived Lhx6(+) cells closely resemble immature interneurons generated from authentic MGE-derived Lhx6(+) cells. We hypothesized that enhancers that are active in the mouse MGE would be useful tools in detecting when ES cells differentiate into MGE cells. Here we demonstrate the utility of enhancer elements [422 (DlxI12b), Lhx6, 692, 1056, and 1538] as tools to mark MGE-like cells in ES cell differentiation experiments. We found that enhancers DlxI12b, 692, and 1538 are active in Lhx6-GFP(+) cells, while enhancer 1056 is active in Olig2(+) cells. These data demonstrate unique techniques to follow and purify MGE-like derivatives from ES cells, including GABAergic cortical interneurons and oligodendrocytes, for use in stem cell-based therapeutic assays and treatments.
    PLoS ONE 05/2013; 8(5):e61956. DOI:10.1371/journal.pone.0061956 · 3.23 Impact Factor
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