Disease relevance of Dlx2

• Dlx1 and Dlx2 expression was seen only in nonneuronal cells of the cochleovestibular ganglion and nerves from stage 21 to stage 32 [1].
• Recent evidence indicates that in utero injection of the E9.5 mouse forebrain with retroviruses encoding wild-type Shh induces the ectopic expression of Dlx2 and severe deformities in the brain [2].

High impact information on Dlx2

• The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator [3].
• In previous experiments, we showed that Sonic hedgehog treatment of forebrain neural explants results in the activation of Dlx-2 and the novel noncoding RNA (ncRNA), Evf-1 [3].
• Evf-2 specifically cooperates with Dlx-2 to increase the transcriptional activity of the Dlx-5/6 enhancer in a target and homeodomain-specific manner [3].
• Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain [4].
• These results show that Dlx-2 controls development of the branchial arches and the forebrain and suggests its role in craniofacial evolution [4].

Biological context of Dlx2

• Dlx2 over-expression regulates cell adhesion and mesenchymal condensation in ectomesenchyme [5].
• Therefore, we propose a model in which rBMP-2 stimulates Dlx-2 expression, which then serves as a necessary transcription factor for Col2alpha1 gene expression through a chondrocyte-specific enhancer fragment [6].
• We have assessed the retinal phenotype of the Dlx1/Dlx2 double knockout mouse, which dies at birth [7].
• Expression begins at embryonic day 12.5 and is maintained until late embryogenesis for Dlx1, while Dlx2 expression extends to adulthood [7].
• Transgenic mice produced with a lacZ reporter construct, containing 3.8 kb upstream sequence of Dlx2, led to the mapping of regulatory regions driving epithelial but not mesenchymal expression in the first branchial arch [8].

Anatomical context of Dlx2

• Notably, in animals carrying either of these genetic backgrounds, genes such as Gsh2 and Dlx2, which are expressed pan-ventrally, as well as Nkx2.1, which demarcates the ventral most aspect of the telencephalon, appear to be largely restored to their wild-type patterns of expression [9].
• By 48 h post-electroporation, the majority of transfected cells formed multicellular aggregates that were found adjacent to the basal side of the neural tube and very few Dlx2 expressing cells migrated to the level of the branchial arches [5].
• Ectopic expression of Dlx2 within the neural tube beginning prior to emigration of neural crest cells at E1.25 drastically inhibits the migration of transfected cells and induces aggregation of transfected neuroepithelial cells within the neural tube at 24 h post-electroporation [5].
• 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].
• We also examined the involvement of Dlx2 in the bone morphogenetic protein-2 (BMP-2) signaling to the type II collagen gene, Col2alpha1, in this cell line [6].

Associations of Dlx2 with chemical compounds

• This approach showed that ectopic expression of Dlx2 and Dlx5 induced the expression of glutamic acid decarboxylases (GADs), the enzymes that synthesize GABA [11].
• Previous reports focusing on embryogenesis of telencephalic neurons in Dlx-1 and Dlx-2 null mice suggested a specific role for these genes in expression of the OB dopamine (DA) phenotype [12].

Regulatory relationships of Dlx2

• Electroporation of the Dlx2 expression construct into branchial arch mesenchyme induced N-cadherin and NCAM, a dramatic increase in cell-cell adhesion relative to controls, and resulted in an increase in mesenchymal condensation [5].
• 5. We provide evidence that Dlx-2 is expressed before Dlx-1, which is expressed before Dlx-5 [13].
• FGF8 also inhibits expression of Dlx2 in the epithelium by a signalling pathway that requires the mesenchyme [8].
• We show that the epithelial expression of Dlx2 is regulated by planar signalling by BMP4, which is coexpressed in distal oral epithelium [8].

Other interactions of Dlx2

• Dlx-1 and Dlx-2 are expressed in two separate regions of the forebrain in an identical pattern [14].
• Dlx1 and Dlx2 are detected in retinal neuroprogenitors by embryonic day (E) 12.5 (Eisenstat et al. [1999] J. Comp. Neurol. 217-237) [10].
• In contrast to Dlx-2 and other vertebrate Distal-less genes, Dlx-3 is not expressed in the central nervous system and is expressed in a highly restricted region of the branchial arches [15].
• Thus, the signalling molecules BMP4 and FGF8 provide the mechanism for maintaining the strict epithelial and mesenchymal expression domains of Dlx2 in the first arch [8].
• Investigation of pan-ventral markers such as Dlx2 also shows that, unlike Shh(-/-), a broad domain of expression of this gene is observed in Shh(-/-);Pax6(-/-) mice [16].

Analytical, diagnostic and therapeutic context of Dlx2

• We have investigated the function of Dlx2 using in ovo electroporation and cell culture [5].
• To determine the function of Dlx-2, we generated a null mutation in mice using gene targeting [4].
• Northern blot experiments on microdissected cells showed the continuing expression of Msx-2 and Dlx-2 in the later stages of dental biomineralization, differentially in epithelial and ectomesenchymal compartments [17].
• In addition, in situ hybridizations were used to define expression patterns of the Dlx 2 and Nkx 2.1 homeobox genes in Gsh-2 mutant mice [18].
• The spatial distribution of Dlx-2 protein during murine tooth development has been investigated using immunohistochemistry with Dlx-2 antibodies [19].

References