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DOT1L deletion impairs the development of cortical Parvalbumin-expressing interneurons

ABSTRACT: Our group has reported that the histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered postmitotic differentiation/maturation.

ORGANISM(S): Mus musculus

PROVIDER: GSE221994 | GEO | 2023/08/01

REPOSITORIES: GEO

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Project description:The Dlx homeodomain transcription factors are implicated in regulating the function of inhibitory GABAergic interneurons; therefore understanding their functions will provide insights into disorders such as epilepsy, mental retardation and autism. Identifying genes that are downstream of Dlx1/2 function and are relevant for the differentiation and survival of GABAergic interneurons. During embryonic development, cortical GABAergic interneurons are generated in the proliferative zone of the medial ganglionic eminence (MGE), from where they migrate to reach their final positions in the cortex. The differentiation of these interneuron precursors is dependent on Dlx genes, as shown by Dlx1/Dlx2 double mutants, which have a block in GABAergic cell differentiation and in cell migration. When interneuron progenitors are isolated from the mutant MGE and growth in culture, they are able to proceed along their differentiation program. However, mutant cells growth in vitro show defects in cell morphogenesis and increased cell apoptosis. We hypothesize that Dlx transcription factors regulate important aspects of GABAergic neuron differentiation such as the formation and growth of axon and dendrites, and the formation of inhibitory synapses. We generated E15.5 mouse embryos that are Dlx1/2 -/- or Dlx1/2 +/?. Genotype was confirmed by PCR. A total of 8 litters were used. For each experiment, we pooled tissue from at least 6 different embryos of the same genotype. We dissected the ventricular and subventricular zones of the MGE (rostral part). This area contains ~1 million of progenitor cells per embryo. We isolated total RNA using the Stratagene RNA Miniprep kit (these samples are called MGE+/ and MGE-/- in our proposal). In addition, we used the same area (ventricular and subventricular zones of the rostral MGE) to perform primary neuronal cultures. Cells were maintained 3 days in vitro. After that, we isolated total RNA using the Stratagene RNA Miniprep kit (samples called primary cells+/ and primary cells-/- in our proposal). We would like to perform gene expression comparison between: 1) MGE+/ and MGE-/-, and 2) primary cells+/ and primary cells-/-.

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DOT1L deletion impairs the development of cortical Parvalbumin-expressing interneurons

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