Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Abstract

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 interferencemediated 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.

Analysis of transcriptional codes for zebrafish dopaminergic neurons reveals essential functions of Arx and Isl1 in prethalamic dopaminergic neuron development

“…The prethalamic DA phenotype we observe in the zebrafish larva may be caused by Arx action at different levels during prethalamic development. This interpretation is consistent with the observation that Arx regulates diverse processes such as regionalization, proliferation, cell differentiation and neuronal migration in different model organisms (Campbell and Tomlinson, 1998;Kitamura et al, 2002;Melkman and Sengupta, 2005;Seufert et al, 2005;Tucker et al, 2005;Yoshihara et al, 2005;Colombo et al, 2007;Friocourt et al, 2008).…”

Molecular Control of Neurogenesis: A View from the Mammalian Cerebral Cortex

“…A large number of transcription factors have been implicated in the proliferation of neural progenitors, and thus ultimately in the control of neuronal numbers in the developing brain. Defects in progenitor divisions and brain growth have been found in mice mutant for the paired homeobox factor Pax6 (Arai et al 2005), the homeobox proteins Lhx2 (Porter et al 1997) and Arx (Friocourt et al 2008), the winged-helix protein Foxg1 (Hanashima et al 2002), and the nuclear receptor Tlx (Roy et al 2004). The target genes that are regulated and the types of progenitor cells that are induced to proliferate by these factors were usually not examined, except in a few cases.…”

Neurons on the Move: Migration and Lamination of Cortical Interneurons

“…For example, loss of function studies for Lhx6 lim-homeobox transcription factor [87,156] and Arx homeodomain transcription factor [157,158] in mouse brain slices have shown impeded tangential migration of interneurons into the cortex. Recently Lhx6 has been shown to mediate its effects through promoting expression of receptors involved in interneuron migration (ErbB4, CXCR4 and CXCR7), and through promoting the expression of transcription factors either known (Arx) or implicated (bMaf, Cux2 and NPAS1) in controlling interneuron development [159].…”