Xenopus aristaless‐related homeobox (xARX) gene product functions as both a transcriptional activator and repressor in forebrain development

Abstract

Mutations in the aristaless-related homeobox (ARX) gene have been found in patients with a variety of X-linked mental retardation syndromes with forebrain abnormalities, including lissencephaly. Arx is expressed in the developing mouse, Xenopus, and zebrafish forebrain. We have used whole-mount in situ hybridization, overexpression, and loss-of-function studies to investigate the involvement of xArx in Xenopus brain development. We verified that xArx is expressed in the prospective diencephalon, as the forebrain is patterned and specified during neural plate stages. Expression spreads into the ventral and medial telencephalon as development proceeds through neural tube and tadpole stages. Overexpression of xArx resulted in morphological abnormalities in forebrain development, including loss of rostral midline structures, syn-or anophthalmia, dorsal displacement of the nasal organ, and ventral neural tube hyperplasia. Additionally, there is a delay in expression of many molecular markers of brain and retinal development. However, expression of some markers, dlx5 and wnt8b, was enhanced in xArx-injected embryos. Loss-of-function experiments indicated that xArx was necessary for normal forebrain development. Expansion of wnt8b expression depended on xArx function as a transcriptional repressor, whereas ectopic expression of dlx5, accompanied by development of ectopic otic structures, depended on function of Arx as a transcriptional activator. These results suggest that Arx acts as a bifunctional transcriptional regulator in brain development. Developmental Dynamics 232:313-324, 2005.

The homeobox gene Arx is a novel positive regulator of embryonic myogenesis

“…Arx has been suggested to be a bifunctional transcription factor, capable of functioning either as a repressor 25,26 or an activator of transcription. 27 The observations reported here suggest that in the context of embryonic myogenesis, Arx positively modulates transcription. The synergism between Arx, Mef2C and MyoD could result from a specific recognition event between the multiprotein complex and a component of the transcriptional machinery or it could result from a concerted reaction in which the assembly of the three factors stabilizes a transcriptional complex, similarly to what was reported for MyoD and Pbx, the latter containing a homeodomain like Arx.…”

The simultaneous loss ofArxandPax4genes promotes a somatostatin-producing cell fate specification at the expense of the α-and β-cell lineages in the mouse endocrine pancreas

“…Thus, through a study combining transgenic, EMSA, ChIP and reporter assay approaches, we have characterized Arx and Pax4 binding sites and have provided evidence that Arx inhibits Pax4 transcription by interacting with the Pax4 enhancer domain, whereas Pax4 antagonizes Arx transcription by binding to a 3′ Arx enhancer region. The finding that both Arx and Pax4 can behave as transcriptional repressors is supported by in vitro studies or analyses performed in C. elegans (Fujitani et al, 1999;Seufert et al, 2004;Smith et al, 1999). However, the detailed mechanisms regulating the prevalence of one factor over the other remain to be elucidated.…”

Inactivation ofArx, the Murine Ortholog of the X-Linked Lissencephaly with Ambiguous Genitalia Gene, Leads to Severe Disorganization of the Ventral Telencephalon with Impaired Neuronal Migration and Differentiation

“…The Arx gene, which encodes a highly conserved homeodomaincontaining transcription factor, maps to the short arm of the mammalian X chromosome (Miura et al, 1997;Campbell and Tomlinson, 1998;Melkman and Sengupta, 2005;Seufert et al, 2005;McKenzie et al, 2007). Mutations of the human ARX gene were initially characterized in patients with X-linked West syndrome, a neurological condition affecting children and young males characterized by mental retardation, infantile spasms, and hypsarrhythmia (Stromme et al, 2002a).…”