Identification of Arx transcriptional targets in the developing basal forebrain

Abstract

Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.

Dynamic spatiotemporal gene expression in embryonic mouse thalamus

“…In addition, weak Ebf3 expression was detected in the mantle region of the Zli (Shimogori et al, 2010). Although Ebf3 has been reported to be a target gene of Arx in the subpalium (Fulp et al, 2008), no expression of Arx was detected in the p2 VZ (Shimogori et al, 2010), suggesting a different molecular function for Ebf3 in the developing thalamus.…”

“…5K-O). It has been reported that Arx directly represses Shox2 expression in the telencephalic ganglionic eminence, which is required for correct differentiation of GABAergic interneurons (Fulp et al, 2008). Arx may play a similar role in the developing prethalamus, which lacks Shox2 expression altogether.…”

Genotype–phenotype correlation in interstitial 6q deletions: a report of 12 new cases

“…Due to the observation of infantile spasms and other epilepsy phenotypes, we compared the brain expressed genes to the Arx conditional knockout transcriptome list [43] and genes in synapse development and function (GO:0045202 and children), as these pathways have recently been associated with infantile spasm pathogenesis [44]. Due to the observation of cerebellar malformations, we also compared the brain-expressed genes for relationships with genes involved in cerebellar development and function (GO:0021549 plus those extracted from expert reviews [45,46]).…”

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

“…We reported a significant reduction of ARX protein abundance in mice modeling the two most common polyalanine tract expansion mutations. 46 Adequate repression of Lmo1, a direct target gene of ARX [47][48][49] was compromised in the brains of these mice during early development. 46 A significant loss of LMO1 repression earlier in development was noted with the more severe polyalanine tract 1 mutation, and correlates with clinical severity displayed by patients with these polyalanine tract mutations.…”