Investigation of genes important in neurodevelopment disorders in adult human brain

Abstract

Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs, SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs. Analysis of DNA interaction sites in neural stem cells reveals high (40-50 %) overlap between proliferating and differentiating cells for each gene in temporal space. Studies in adult brain demonstrate that consensus sites are similar to NSCs but occur at different genomic locations. We also performed expression analyses using BrainSpan data for NDD-associated genes SATB2, EHMT1, FMR1, MECP2, MBD5, CTNND2, RAI1, CHD8, GRIN2A, GRIN2B, TCF4, SCN2A, and DYRK1A and find high expression of these genes in adult brain, at least comparable to developing human brain, confirming that genes associated with NDDs likely have a role in adult tissue. Adult function of genes associated with NDDs might be important in clinical disease presentation and may be suitable targets for therapeutic intervention.

Higher O-GlcNAc Levels Are Associated with Defects in Progenitor Proliferation and Premature Neuronal Differentiation during in-Vitro Human Embryonic Cortical Neurogenesis

“…Over the years, different genes have been shown to be involved in the regulation of cell proliferation and differentiation during cortical neurogenesis and defects in their expression have been shown to be associated with different neurodevelopmental disorders (Chen et al, 2014 ; Gigek et al, 2015 ; Maussion et al, 2015 ). T-box brain 1 ( TBR1 ) is a transcription factor expressed at a high level in early born deep layer cortical neurons and was shown to be required for differentiation of cortical progenitor cells (Hevner et al, 2001 ; Bedogni et al, 2010 ).…”

Netrin G1: its downregulation in the nucleus accumbens of cocaine‐conditioned mice and genetic association in human cocaine dependence

“…Interestingly, we have recently examined, from fetal to adult stages in several brain regions, the spatial and temporal expression patterns of genes whose mutations were found in neurodevelopmental disorders. The expression profiles suggest that all these genes are continuously expressed, and like the NTNG1 gene, have various functions depending on the period of life (Maussion et al ). The expression of either neurodevelopmental disorders or psychiatric diseases may rely on one or several gene mutations including in the NTNG1 gene.…”

Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis complex (TSC): evidence from layer-specific marker expression

“…Additionally, it was suggested that they disappear after 3 months of age in the human brain [ 20 , 29 ]. On the contrary, it was also reported that Satb2+ cells remain as a subpopulation in the upper cortical layers of the human brain but also extending towards layer 5 (having a predisposition for the frontal lobe) [ 30 , 31 ]. In our study, expression of Satb2 was detected in L2, 3, and 5 in both perilesional samples and postmortem controls.…”