Disease relevance of Dlx1

• Dlx1 and Dlx2 expression was seen only in nonneuronal cells of the cochleovestibular ganglion and nerves from stage 21 to stage 32 [1].
• We show here that in vertebrate cells, Dlx genes appear to be part of a regulatory cascade initiated by acute lymphoblastic leukemia (ALL)-1, a master regulator gene whose disruption is implicated in several human acute leukemias [2].

High impact information on Dlx1

• Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes [3].
• One of the first of these was identified in the intergenic region between the Dlx-5 and Dlx-6 genes, members of the Dlx/dll homeodomain-containing protein family [4].
• Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy [5].
• Dlx1 mutant mice show generalized electrographic seizures and histological evidence of seizure-induced reorganization, linking the Dlx1 mutation to delayed-onset epilepsy associated with interneuron loss [5].
• Disrupting differentiation in the embryonic basal telencephalon (lateral and medial ganglionic eminences) through loss of Dlx1/2 homeobox function blocks the migration of virtually all GABAergic interneurons to the hippocampus [6].

Biological context of Dlx1

• To determine if the overlaps are a result of the conservation of enhancer sequences between paralogous clusters, we compared the Dlx1/2 and the Dlx5/Dlx6 intergenic regions from human, mouse, zebrafish, and from two pufferfish, Spheroides nephelus and Takifugu rubripes [7].
• Although Dlx1 knockout mice did not display any obvious developmental defects in thymus or thymocyte development, the expression of these homeobox genes in neural crest derivatives suggests a possible role in cell migration and development that may overlap with other homeobox genes [8].
• Dlx homeobox genes of vertebrates are generally arranged as three bigene clusters on distinct chromosomes [7].
• Little is known of the regulatory architecture that is responsible for Dlx gene expression in developing arches [9].
• LacZ transgene expression containing I12a is restricted to a subset of Dlx-expressing ectomesenchyme in the first arch [9].

Anatomical context of Dlx1

• We have identified two distinct cis-acting regulatory sequences, I12a and I56i, in the intergenic regions of the Dlx1/2 and Dlx5/6 clusters that act as enhancers in the arch mesenchyme [9].
• Our results support a possible role for Dlx1 and Dlx2 in inner retinal development and in the terminal differentiation and/or maintenance of INL interneurons and ganglion cells in the adult [10].
• Identification and characterization of a novel transcript down-regulated in Dlx1/Dlx2 and up-regulated in Pax6 mutant telencephalon [11].
• The expression of Dlx1 and Arx in the presumptive ventral thalamus extended as far as ZLI and overlapped with that of Brx1 [12].
• Significantly, Dlx1 is expressed in the third branchial arch, which contributes to the thymus [8].

Associations of Dlx1 with chemical compounds

• Despite late appearance of gamma-aminobutyric acid (GABA)ergic cells in the dorsal lateral geniculate nucleus of mice, no Dlx genes, which promote formation of a GABAergic phenotype elsewhere, were detected in dorsal thalamus [13].
• These findings suggest that Dlx-1 and -2 do not play a direct role in DA phenotypic differentiation and TH gene regulation in adult OB [14].

Regulatory relationships of Dlx1

• Dlx1 is a member of the distal-less homeobox gene family that has been shown to regulate embryonic craniofacial development [8].
• Dlx-5 appears to be co-expressed with Dlx-1 and -2 in the SVZ, but is also expressed in the postmitotic cells of the mantle [15].
• Ectopic expression of the Dlx genes induces glutamic acid decarboxylase and Dlx expression [16].
• Interestingly, calretinin-expressing bipolar interneurons were nearly absent from cortical cultures of Dlx1/2 mutants [17].
• Therefore, our results suggest evolutionarily conserved functions of Dlx genes in regulating Arx expression between Drosophila and vertebrates [18].
• We demonstrate that Dlx1&2 negatively regulate Olig2-dependant OPC formation and that Mash1 promotes OPC formation by restricting the number of Dlx+ progenitors [19].

Other interactions of Dlx1

• Dlx-1 and Dlx-2 are expressed in two separate regions of the forebrain in an identical pattern [20].
• The Gbx-2 gene is expressed in four domains, two of which share sharp boundaries with the domains of the Dlx genes [20].
• Dlx1/2 double homozygous mutants formed ventral thalamic neurons, but these neurons lacked PAX6, ISL1, and TH expression [21].
• The correlation of DLX2 with GABA expression in the mouse retina closely mirrors the relationship of DLX2 to GABAergic neuronal differentiation in the embryonic forebrain, including neocortex, olfactory bulb and hippocampus, signifying a conservation of function of Dlx genes in the developing central nervous system [10].
• Transcripts for multiple Dlx family members and Lhx2 were repeatedly detected in this screen [8].

Analytical, diagnostic and therapeutic context of Dlx1

• Identification of a direct Dlx homeodomain target in the developing mouse forebrain and retina by optimization of chromatin immunoprecipitation [22].
• Cell transplantation analysis demonstrates that interneuron loss reflects cell-autonomous functions of Dlx1 [5].
• To test whether the Dlx genes are sufficient to induce some aspects of the phenotype of GABAergic neurons, we adapted the electroporation method to ectopically express DLX proteins in slice cultures of the mouse embryonic cerebral cortex [16].
• DESIGN: Postmortem sections containing the thalamic mediodorsal nucleus were subjected to in situ hybridization with mouse Dlx1 and human SHOX2 RNA probes [23].
• Because beta-galactosidase activity persists long after expression of the Dlx genes and the transgene becomes undetectable, we were able to analyse the beta-galactosidase-positive cell population of the mature cortex through X-gal staining and immunohistochemistry [24].

References