TY - JOUR
T1 - Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons
AU - Colasante, Gaia
AU - Collombat, Patrick
AU - Raimondi, Valentina
AU - Bonanomi, Dario
AU - Ferrai, Carmelo
AU - Maira, Mario
AU - Yoshikawa, Kazuaki
AU - Mansouri, Ahmed
AU - Valtorta, Flavia
AU - Rubenstein, John L R
AU - Broccoli, Vania
PY - 2008/10/15
Y1 - 2008/10/15
N2 - 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.
AB - 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.
KW - Basal forebrain
KW - Basal ganglia
KW - Development
KW - Epilepsy
KW - GABAergic neuron
KW - Neuronal progenitor cell
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UR - http://www.scopus.com/inward/citedby.url?scp=54849441959&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1283-08.2008
DO - 10.1523/JNEUROSCI.1283-08.2008
M3 - Article
C2 - 18923043
AN - SCOPUS:54849441959
VL - 28
SP - 10674
EP - 10686
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 42
ER -