Dlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma-aminobutyric acid (GABA)-expressing neurons of the forebrain, including local-circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single-nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating Dlx5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease.
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"For example, a rare variant implicated in autism was found in an enhancer that is active during forebrain development [Poitras et al., 2010]. The variant that may increase risk for autism alters binding of regulatory TFs and reduces enhancer activity in the developing forebrain [Poitras et al., 2010]. Another study focused on an enhancer that underwent accelerated evolution on the human lineage, after splitting from that of chimpanzees [Boyd et al., 2015]. "
"Evf2 was discovered in the developing mouse forebrain and it is transcribed from the ultra-conserved Dlx5/6 region encoding the homeodomain transcription factors DLx5 and DLx6 (Feng et al., 2006). Dlx homeobox genes products play a crucial role in migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma-aminobutiric acid (GABA)-expressing neurons of the forebrain, including localcircuit cortical interneurons (Poitras et al., 2010). Interneurons play a vital role in modulating the activity of the cerebral cortex and they rely on the enzyme glutamic acid decarboxylase 67 (GAD67) for the synthesis of GABA (Addington et al., 2005), the major inhibitory neurotransmitter in the brain. "
[Show abstract][Hide abstract]ABSTRACT: Several lines of evidence indicate that schizophrenia has a strong genetic component. But the exact nature and functional role of this genetic component in the pathophysiology of this mental illness remains a mystery. Long non-coding RNAs (lncRNAs) are a recently discovered family of molecules that regulate gene transcription through a variety of means. Consequently, lncRNAs could help us bring together apparent unrelated findings in schizophrenia; namely, genomic deficiencies on one side and neuroimaging, as well as postmortem results on the other. In fact, the most consistent finding in schizophrenia is decreased brain size together with enlarged ventricles. This anomaly appears to originate from shorter and less ramified dendrites and axons. But a decrease in neuronal arborizations cannot explain the complex pathophysiology of this psychotic disorder; however, dynamic changes in neuronal structure present throughout life could. It is well recognized that the structure of developing neurons is extremely plastic. This structural plasticity was thought to stop with brain development. However, breakthrough discoveries have shown that neuronal structure retains some degree of plasticity throughout life. What the neuroscientific field is still trying to understand is how these dynamic changes are regulated and lncRNAs represent promising candidates to fill this knowledge gap. Here, we present evidence that associates specific lncRNAs with schizophrenia. We then discuss the potential role of lncRNAs in neurostructural dynamics. Finally, we explain how dynamic neurostructural modifications present throughout life could, in theory, reconcile apparent unrelated findings in schizophrenia.
"Dlx1/2 antagonize MECP2 repression of Dlx5 (Berghoff et al., 2013). A Dlx5/6 ei SNP that disrupts DLX1/2 binding was identified in an autistic proband (Poitras et al., 2010). Given the global DNA-binding properties of MECP2, it has been difficult to envision how this may cause such specific neurological phenotypes, as in Rett syndrome. "