Cell-autonomous roles of ARX in cell proliferation and neuronal migration during corticogenesis.
The aristaless-related homeobox (ARX) gene has been implicated in a wide spectrum of disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. To better understand its role in corticogenesis, we used in utero electroporation to knock down or overexpress ARX. We show here that targeted inhibition of ARX causes cortical progenitor cells to exit the cell cycle prematurely and impairs their migration toward the cortical plate. In contrast, ARX overexpression increases the length of the cell cycle. In addition, we report that RNA interference-mediated inactivation of ARX prevents cells from acquiring multipolar morphology in the subventricular and intermediate zones, resulting in decreased neuronal motility. In contrast, ARX overexpression appears to promote the development of tangentially oriented processes of cells in the subventricular and intermediate zones and affects radial migration of pyramidal neurons. We also demonstrate that the level of ARX expression is important for tangential migration of GABA-containing interneurons, because both inactivation and overexpression of the gene impair their migration from the ganglionic eminence. However, our data suggest that ARX is not directly involved in GABAergic cell fate specification. Overall, these results identify multiple and distinct cell-autonomous roles for ARX in corticogenesis.
Friocourt
Gaëlle
G
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
Kanatani
Shigeaki
S
Tabata
Hidenori
H
Yozu
Masato
M
Takahashi
Takao
T
Antypa
Mary
M
Raguénès
Odile
O
Chelly
Jamel
J
Férec
Claude
C
Nakajima
Kazunori
K
Parnavelas
John G
JG
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D002522:Chlorocebus aethiops; D000089662:Doublecortin Protein; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C469265:ARX protein, mouse; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D001973:Bromodeoxyuridine