Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice

Abstract

ARX (the aristaless-related homeobox gene) is a transcription factor that participates in the development of GABAergic and cholinergic neurons in the forebrain. Many ARX mutations have been identified in X-linked lissencephaly and mental retardation with epilepsy, and thus ARX is considered to be a causal gene for the two syndromes although the neurobiological functions of each mutation remain unclear. We attempted to elucidate the causal relationships between individual ARX mutations and disease phenotypes by generating a series of mutant mice. We generated three types of mice with knocked-in ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation [P353L and 333ins(GCG)7]. Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and lifespan from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum and ventral forebrain nuclei when compared with wild-type mice. Present findings that reveal a causal relationship between ARX mutations and the pleiotropic phenotype in mice, suggest that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors.

Tbr2-positive intermediate (basal) neuronal progenitors safeguard cerebral cortex expansion by controlling amplification of pallial glutamatergic neurons and attraction of subpallial GABAergic interneurons

“…This might be explained by the reduced number of INPs, as a consequence of a smaller pool of radial glial cells, which support the migration of only a minor fraction of subpallial GABAergic interneurons, balancing the ratio between glutamatergic and GABAergic neurons, and thereby their respective excitatory and inhibitory tones. In contrast, congenic cortical malformations associated with cell migration defects, like various forms of lissencephaly, are strongly associated with epilepsy or infantile spasms, which might result from the unbalanced loss of cortical GABAergic neurons prevented from reaching the cortex from the subpallium (Kato and Dobyns 2003;Kappeler et al 2006;Kitamura et al 2009). Thus, INPs are a crucial cellular hub connecting direct and indirect cortical expansion, and the tripartite layering organization of the developing cortex-with the VZ, SVZ, and CP-provides an ideal set of compartments where tangential migration can take place with minimal interference on local cell proliferation and differentiation.…”

“…In fact, an altered balance between these two populations might result in death or lead to a large variety of neurological symptoms ranging from untreatable epilepsy to psychiatric disorders (Powell et al 2003;Kalanithi et al 2005;Kitamura et al 2009;Belforte et al 2010). During development of the mammalian brain, the cerebral cortex undergoes enormous expansion, yet nevertheless preserves the right balance between excitatory and inhibitory neurons.…”

Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

“…26,27 However, there is no data as yet available regarding the transmission of the mutant alleles. Provided the TRD holds true in these knock-in mice, it will provide an opportunity to investigate the molecular mechanisms of this phenomenon in greater detail.…”

A Toolbox for Spatiotemporal Analysis of Voltage-Sensitive Dye Imaging Data in Brain Slices

“…Anatomical abnormalities have been observed in mouse models of some, but not all, mutations in the Arx gene [8], [14], [15]. To determine if the Arx −/+ ;Dlx5/6 CIG mutation produces anatomical abnormalities in the adult mouse hippocampus, we compared the anatomy of mutant slices to the anatomy of control slices.…”