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The Journal of Neuroscience, October 15, 2008, 28(42):10674-10686; doi:10.1523/JNEUROSCI.1283-08.2008
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Development/Plasticity/Repair
Arx Is a Direct Target of Dlx2 and Thereby Contributes to the Tangential Migration of GABAergic Interneurons
Gaia Colasante,1,2 * Patrick Collombat,4 * Valentina Raimondi,1,2 Dario Bonanomi,1 Carmelo Ferrai,1 Mario Maira,5 Kazuaki Yoshikawa,6 Ahmed Mansouri,4 Flavia Valtorta,1,3 John L. R. Rubenstein,5 andVania Broccoli1,2 1Department of Biological and Technological Research, San Raffaele Scientific Institute, 2Stem Cell Research Institute (SCRI), and 3"Vita e Salute" San Raffaele University, 20132 Milan, Italy, 4Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany, 5Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, and 6Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan
Correspondence should be addressed to Vania Broccoli, Stem Cell Research Institute (SCRI), San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Email: broccoli.vania{at}hsr.it
The Arx transcription factor is expressed in the developing ventral telencephalon and subsets of its derivatives. Mutation of human ARX ortholog causes neurological disorders including epilepsy, lissencephaly, and mental retardation. We have isolated the mouse Arx endogenous enhancer modules that control its tightly compartmentalized forebrain expression. Interestingly, they are scattered downstream of its coding region and partially included within the introns of the downstream PolA1 gene. These enhancers are ultraconserved noncoding sequences that are highly conserved throughout the vertebrate phylum. Functional characterization of the Arx GABAergic enhancer element revealed its strict dependence on the activity of Dlx transcription factors. Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression, suggesting that Arx is a key mediator of Dlx function. To further elucidate the mechanisms involved, a combination of gain-of-function studies in mutant Arx or Dlx tissues was pursued. This analysis provided evidence that, although Arx is necessary for the Dlx-dependent promotion of interneuron migration, it is not required for the GABAergic cell fate commitment mediated by Dlx factors. Although Arx has additional functions independent of the Dlx pathway, we have established a direct genetic relationship that controls critical steps in the development of telencephalic GABAergic neurons. These findings contribute elucidating the genetic hierarchy that likely underlies the etiology of a variety of human neurodevelopmental disorders.
Key words: basal forebrain; development; epilepsy; GABAergic neuron; neuronal progenitor cell; basal ganglia
Received March 25, 2008; revised June 30, 2008; accepted Aug. 16, 2008.
Correspondence should be addressed to Vania Broccoli, Stem Cell Research Institute (SCRI), San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Email: broccoli.vania{at}hsr.it
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