Developmental interneuron subtype deficits after targeted loss of Arx

BMC Neuroscience

Research Article

C. Nicole Sunnen¹  MacLean Pancoast Nasrallah²  Jeffrey A. Golden³  Eric D. Marsh⁴  Caroline Walsh⁵  Kaitlin A. Murray⁵  Almedia McCoy⁵ 

[1] Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA;Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA;Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., 02115, Boston, MA, USA;Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Division of Child Neurology, Children’s Hospital of Philadelphia, Room 502E, Abramson Research Building, 3615 Civic Center Boulevard, 19014, Philadelphia, PA, USA;Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA;Division of Child Neurology, Children’s Hospital of Philadelphia, Room 502E, Abramson Research Building, 3615 Civic Center Boulevard, 19014, Philadelphia, PA, USA;

关键词: Interneuron;    Development;    Migration;   

DOI  :  10.1186/s12868-016-0265-8

 received in 2015-09-11, accepted in 2016-06-03,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundAristaless-related homeobox (ARX) is a paired-like homeodomain transcription factor that functions primarily as a transcriptional repressor and has been implicated in neocortical interneuron specification and migration. Given the role interneurons appear to play in numerous human conditions including those associated with ARX mutations, it is essential to understand the consequences of mutations in this gene on neocortical interneurons. Previous studies have examined the effect of germline loss of Arx, or targeted mutations in Arx, on interneuron development. We now present the effect of conditional loss of Arx on interneuron development.ResultsTo further elucidate the role of Arx in forebrain development we performed a series of anatomical and developmental studies to determine the effect of conditional loss of Arx specifically from developing interneurons in the neocortex and hippocampus. Analysis and cell counts were performed from mouse brains using immunohistochemical and in situ hybridization assays at 4 times points across development. Our data indicate that early in development, instead of a loss of ventral precursors, there is a shift of these precursors to more ventral locations, a deficit that persists in the adult nervous system. The result of this developmental shift is a reduced number of interneurons (all subtypes) at early postnatal and later time periods. In addition, we find that X inactivation is stochastic, and occurs at the level of the neural progenitors.ConclusionThese data provide further support that the role of Arx in interneuron development is to direct appropriate migration of ventral neuronal precursors into the dorsal cortex and that the loss of Arx results in a failure of interneurons to reach the cortex and thus a deficiency in interneurons.

【 授权许可】

CC BY   
© The Author(s) 2016