Developmental interneuron subtype deficits after targeted loss of Arx.
Aristaless-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.



To 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.



These 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.
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. marshe@email.chop.edu.|Division of Child Neurology, Children's Hospital of Philadelphia, Room 502E, Abramson Research Building, 3615 Civic Center Boulevard, Philadelphia, PA, 19014, USA. marshe@email.chop.edu.|Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. marshe@email.chop.edu.
Eric D
0000-0003-3264-0902
ED
Marsh
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.
MacLean Pancoast
MP
Nasrallah
Division of Child Neurology, Children's Hospital of Philadelphia, Room 502E, Abramson Research Building, 3615 Civic Center Boulevard, Philadelphia, PA, 19014, USA.
Caroline
C
Walsh
Division of Child Neurology, Children's Hospital of Philadelphia, Room 502E, Abramson Research Building, 3615 Civic Center Boulevard, Philadelphia, PA, 19014, USA.
Kaitlin A
KA
Murray
Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
C
C
Nicole Sunnen
Division of Child Neurology, Children's Hospital of Philadelphia, Room 502E, Abramson Research Building, 3615 Civic Center Boulevard, Philadelphia, PA, 19014, USA.
Almedia
A
McCoy
Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. jagolden@partners.org.|Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. jagolden@partners.org.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA. jagolden@partners.org.
Jeffrey A
JA
Golden
D000818:Animals; D064032:Calbindin 2 / Q000378:metabolism; D064026:Calbindins / Q000378:metabolism; D002452:Cell Count; D002465:Cell Movement / Q000502:physiology; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
C469265:ARX protein, mouse; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D064026:Calbindins; D018398:Homeodomain Proteins; D009478:Neuropeptide Y; D010320:Parvalbumins; D014157:Transcription Factors
Development; Interneuron; Migration