T‐Brain‐1 – A Potential Master Regulator in Autism Spectrum Disorders

Abstract

T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in Tbr1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism.

TBR1 regulates autism risk genes in the developing neocortex

“…TBR1's role as a master regulator of cortical development has long made it a candidate regulator of ASD genes (Bedogni et al 2010;Chuang et al 2015); here, we measure its binding genomewide in the developing cortex and confirm its role in regulating other high-confidence ASD genes for the first time. The enrichment of TBR1 ChIP-seq peaks adjacent to high-confidence ASD genes suggests that TBR1 can be used to select a subset of probable ASD genes that are less tolerant to LoF alleles and could be more relevant to ASD (Table 3).…”

Differential neuronal and glial expression of nuclear factor I proteins in the cerebral cortex of adult mice

“…Considering that NFI proteins have recently been implicated in diseases such as autism and cancer (Chuang, Huang, & Hsueh, ; Fancy, Glasgow, Finley, Rowitch, & Deneen, ; Genovesi et al, ; Glasgow et al, ; Ho et al, ; Idbaih et al, ; Lacroix et al, ; Lastowska et al, ; Le‐Niculescu et al, ; Lee et al, ; Song et al, ; Stringer et al, ; Suwarnalata et al, ; Tsang et al, ; Vyazunova et al, ), a thorough analysis of their expression in the adult brain is required. Here, we examined both region and cell‐type‐specific expression in the adult mouse cerebral cortex using antibodies specific for NFIA, NFIB, and NFIX.…”

Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice

“…25 Human genetic studies have indicated that TBR1 is a high-confidence risk factor for ASD and intellectual disability. [26][27][28][29][30][31] Because interaction with CASK increases the transcriptional activity of TBR1 to upregulate Grin2b expression, 14,24,[32][33][34] the TBR1-GRIN2B pathway is likely involved in the function of CASK in regulating intellectual ability. Our previous study showed that the Thr724 (T724) residue of rat CASK protein is the protein kinase A (PKA) phosphorylation site.…”