Abstract
Imprinting is an epigenetic mechanism that restrains the expression of about 100 genes to one allele depending on its parental origin. Several imprinted genes are implicated in neurodevelopmental brain disorders, such as autism, Angelman, and Prader-Willi syndromes. However, how expression of these imprinted genes is regulated during neural development is poorly understood. Here, using single and double KO animals for the transcription factors Neurogenin2 (Ngn2) and Achaete-scute homolog 1 (Ascl1), we found that the expression of a specific subset of imprinted genes is controlled by these proneural genes. Using in situ hybridization and quantitative PCR, we determined that five imprinted transcripts situated at the Dlk1-Gtl2 locus (Dlk1, Gtl2, Mirg, Rian, Rtl1) are upregulated in the dorsal telencephalon of Ngn2 KO mice. This suggests that Ngn2 influences the expression of the entire Dlk1-Gtl2 locus, independently of the parental origin of the transcripts. Interestingly 14 other imprinted genes situated at other imprinted loci were not affected by the loss of Ngn2. Finally, using Ngn2/Ascl1 double KO mice, we show that the upregulation of genes at the Dlk1-Gtl2 locus in Ngn2 KO animals requires a functional copy of Ascl1. Our data suggest a complex interplay between proneural genes in the developing forebrain that control the level of expression at the imprinted Dlk1-Gtl2 locus (but not of other imprinted genes). This raises the possibility that the transcripts of this selective locus participate in the biological effects of proneural genes in the developing telencephalon.
Highlights
The cerebral cortex is populated by two main neuronal classes, pyramidal neurons and interneurons that represent respectively 85% and 15% of cortical neurons.Two distinct, though tightly linked processes, control the development and placement of these neurons within the cortex
In a microarray screen to identify Ngn2 targets (JS, TB and PV, unpublished data), we observed that the non-coding RNA encoded by the imprinted gene Gtl2 (Gene trap locus 2, known as Maternally expressed gene 3) was highly upregulated in the dorsal telencephalon of Ngn2 KO mice
To shed light on Gtl2 localization and infer about its function in the normal developing telencephalon, we performed in situ hybridizations (ISH) on WT animals
Summary
The cerebral cortex is populated by two main neuronal classes, pyramidal neurons and interneurons that represent respectively 85% and 15% of cortical neurons.Two distinct, though tightly linked processes, control the development and placement of these neurons within the cortex. On one hand, ‘spatial patterning’ by which the telencephalon is regionally subdivided into defined morphological and molecular progenitor territories, thereby underlying the generation of future interneurons and pyramidal neurons [1,2]. Pyramidal neurons and interneurons originate through two distinct embryonic structures, the dorsal and the ventral telencephalon respectively [1,3]. The proneural genes Ngn and Ascl are respectively expressed in the dorsal and ventral telencephalon, where they determine the regional identity of neural progenitors [5,6]. In Ngn KO mice, dorsal progenitors are partially respecified towards a ventral phenotype as a result of Ascl ectopic expression in the presumptive cortex [5]. Ngn and Ascl regulate temporal patterning [7,8] and coordinate a wide range of basic cellular processes such as cell cycle exit, migration or neuronal connectivity [9,10]
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