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Catch Me if You Can: An elusive underpinning for Arx(GCG)10+7-mediated apoptosis in X-linked infantile spasms syndrome

Posted by , on 3 June 2020

This post highlights the approach and finding of a new research article published by Disease Models and Mechanisms (DMM). This feature is written by Olivia Howell as apart of a seminar at The University of Alabama (taught by DMM Editorial Board member, Prof. Guy Caldwell) on current topics related to use of animal and cellular model systems in studies of human disease.


Within the brain, anomalies in neuronal migration can precipitate aberrant phenotypes such as epilepsy, a disorder in which atypical neuronal circuitry induces recurrent seizures alongside additional neurological abnormalities2,3. X-linked infantile spasms syndrome (ISSX) is one such debilitating epileptic subtype hallmarked by intellectual disability and intractable seizures that first present in infancy4. Previous work has established a causative link between ISSX and mutations in the Aristaless-related homeobox (ARX) – a gene that influences tangential and radial migration of some GABAergic interneurons vital for repressing excitatory neuronal signaling5,6,7,8. Despite recent progress, the precise pathogenesis of ISSX as well as safe, specific and effective treatments remain elusive. Consequently, characterization of early progenitor interneurons is crucial to understanding and managing this disorder.

In this report, Siehr et al. hypothesized that recapitulating pancreatic ARX functionality within a developing neuronal framework would elucidate the role of this gene in ISSX and the means by which E2 and ACTH mediate their anti-epileptic effects7. They therefore utilized an Arx(GCG)10+7 mouse model that recapitulates the ISSX phenotype to uncover temporally increased levels of apoptosis within the neocortex of Arx-mutant mice. Because this abnormal pattern of apoptosis could not be ascribed to ARX cell death, Siehr et al. deemed it non-cell autonomous in nature. While the affected cell population remains unascertained, Siehr and colleagues have definitively eliminated cortical non-ARX expressing interneurons and inflammatory processes from consideration by examining postnatal neuronal survival and neuroinflammation.

In regard to therapeutics, E2 was found to mitigate ARX+ cell density and ISSX seizure phenotype but proved unable to rescue increased apoptosis – rendering the utility of this drug unresolved. Moreover, the unanticipated failure of ACTH to rescue ARX (GCG)10+7 mutants from seizure phenotype may ultimately lay the groundwork to model intractable ACTH-resistant ISSX cases and thereby explore alternative ISSX treatments.

Notably, the authors herein report the first known observation of ARX-associated apoptosis in an ARX (GCG)10+7 rodent model for ISSX – a corroboration of findings in pancreatic tissue expressing aberrant ARX that highlights the relevance of cross-organ systems research.  While too soon to conclude that apoptosis contributes to ISSX pathogenesis, these results underscore the broad, varied and lingering effects of ARX upon neuronal structure and development. Accordingly, one can expect that subsequent pharmacodynamic studies of E2 and ACTH may ascertain their therapeutic relevance to ISSX while also elucidating the relationship between ARX-mediated apoptosis and subclinical molecular features of ISSX pathology.




  1. Siehr, M., Massey, C. and Noebels, J. L. (2020). Arx expansion mutation perturbs cortical development by augmenting apoptosis without activating innate immunity in a mouse model of X-​Linked Infantile Spasms Syndrome. Dis Model Mech 13, 1-10.
  1. Hwang, H. M., Ku, R. Y. and Hashimoto-Toril, K. (2019) Prenatal environment that affects neuronal migration. Cell Dev. Biol. 7, 138. 
  1. Jackson, M. R., Lee, K., Mattiske, T., Jaehne, E. J., Ozturk, E., Baune, B. T., O’Brien, T. J., Jones, N. and Shoubridge, C. (2017). Extensive phenotyping of two ARX polyalanine expansion mutation mouse models that span clinic al spectrum of intellectual disability and epilepsy. Dis. 105, 245-256. 
  1. Olivetti, P. R. and Noebels, J. L. (2012). Interneuron, interrupted: molecular pathogenesis of ARX mutation and X-linked infantile spasms. Opin. Neurobiol. 22, 859-865. 
  1. Olivetti, P. R., Maheshwari, A. and Noebels, J. L. (2014). Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome. Transl. Med. 6, 1-10. 
  1. Poirier, K., Van Esch, H., Friocourt, G., Saillour, Y., Bahi, N., Backer, S., Souil, E., Castelnau-Ptakhine, L., Beldjord, C., Francis, F. et al. (2003) Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons. Brain Res. Mol. Brain Res. 122, 35-46. 
  1. Wilcox, C. L., Terry, N. A. and May, C. L. (2013). Arx polyalanine expansion in mice leads to reduced pancreatic a -Cell specification and increased a-Cell death. PLoS ONE 8, e78741. 
  2. Mattiske, T., Lee, K., Gecz, J., Friocourt, G. and Shoubridge, C. (2016). Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene. Mol. Genet. 25, 5433-5443.




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