Disease relevance of Pax6

• Aphakia (ak), a mouse mutation affecting early eye development: fine mapping, consideration of candidate genes and altered Pax6 and Six3 gene expression pattern [1].
• Activation of Pax4 resulted in the expression of the late-stage transcription factors, including Pax6, Isl-1, and MafA, and generated a gene expression profile for WB-1A cells similar to that of functional rat insulinoma INS-1 cells [2].
• Mutations in Pax6 function result in eye malformations known as Aniridia in humans and Small eye syndrome in mice [3].
• After differential screening of a cDNA library constructed from quail neuroretina cells infected with the v-myc containing avian retrovirus MC29, we have isolated a cDNA clone Pax-QNR, homologous to the murine Pax6 which is mutated in the autosomal dominant mutation small eye (Sey) of the mouse and aniridia in man [4].
• Pax6(-/-) cells contributed only poorly to the neural retina, forming small clumps of cells that were normally restricted to the ganglion cell layer at E16 [5].
• We suggest a chronic wound model for Pax6-related corneal diseases, in which oxidative stress underlies a positive feedback mechanism by depleting nuclear Pax6, delaying wound healing, and activating cell signalling pathways that lead to metaplasia of the corneal epithelium [6].

High impact information on Pax6

• Pax6 is required for the multipotent state of retinal progenitor cells [7].
• Our findings demonstrate furthermore that Pax6 directly controls the transcriptional activation of retinogenic bHLH factors that bias subsets of RPCs toward the different retinal cell fates, thereby mediating the full retinogenic potential of RPCs [7].
• Upon Pax6 inactivation, the potential of RPCs becomes entirely restricted to only one of the cell fates normally available to RPCs, resulting in the exclusive generation of amacrine interneurons [7].
• Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling [8].
• Third, a proportion of Sey/+ Smalleye mice, heterozygous for a nonsense mutation in murine Pax-6, have an ocular phenotype resembling Peters' anomaly [9].

Biological context of Pax6

• Here we show that high-level expression of at least one functional allele of either of the homeobox genes Emx2 or Pax6 in the dorsal telencephalon is necessary and sufficient to stably activate morphogenesis of cerebral cortex and to repress that of adjacent structures, such as striatum [10].
• These results link Pax6 to the process of retinal neurogenesis and provide the first molecular correlate for the dosage-sensitivity of the Pax6 phenotype [11].
• Taken together, our results provide evidence that Necab is genetically downstream of Pax6 and that it is a part of a signal transduction pathway in retina development [12].
• Pax6 occupies the binding site in the proximal promoter in vivo as demonstrated by the chromatin immunoprecipitation assay [13].
• Mutations in this site eliminate Pax6 binding as well as stimulation of the Optimedin promoter activity by Pax6 in transfection experiments [13].

Anatomical context of Pax6

• In mice lacking Pax6, progenitor cells generate neurons characteristic of exposure to greater Shh activity [14].
• In Nkx2.2 mutants, Pax6 expression is unchanged but cells undergo a ventral-to-dorsal transformation in fate and generate motor neurons rather than interneurons [14].
• Furthermore, expression of Pax6 and Six3, molecular markers for lens induction, were decreased in the Frs2alpha(2F/2F) presumptive lens ectoderm [15].
• This analysis revealed severe defects in forebrain regions where Pax6 is specifically expressed [16].
• Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6 [17].

Associations of Pax6 with chemical compounds

• Gel shift assays using lens nuclear extracts demonstrated interactions of Pax6, Maf, and retinoic acid nuclear receptor proteins with two lens-specific regions, the distal LSR1 (-147/-118) and proximal LSR2 (-78/-40), of the alphaB-crystallin promoter [18].
• We conclude that Otx2 and Pax6 are key molecules involved in conserved mechanisms of ANF gene regulation [19].
• The region where the astrocyte-specific glutamate transporter is strongly expressed in the ventral radial glial cells is closely related to the Pax6-expressing domain, and the weakly expressing region corresponding to the Nkx2.2-expressing domain [20].
• Thus, Pax6 delimits the appropriate proliferative zone for GABA INs and regulates their numbers and distributions by repressing the ventral fates of dTel progenitors and progeny [21].
• Transcription Factors Pax6 and AP-2alpha Interact To Coordinate Corneal Epithelial Repair by Controlling Expression of Matrix Metalloproteinase Gelatinase B [22].

Physical interactions of Pax6

• A pancreatic islet cell-specific enhancer sequence (PISCES) shared by the rat insulin-I, glucagon, and somatostatin genes binds the paired domain-containing transcription factor Pax6 and confers strong transcriptional activity in pancreatic islet cell lines [23].
• In agreement with the conservation of the optimal binding sequences among the Pax family transcription factors, Pax4 could bind to the potential binding sites for Pax6, another member of the Pax family also involved in endocrine pancreas development [24].
• In this report, we show that Pax6 additionally binds the glucagon gene promoter G1-element and forms a transcriptionally active complex with another homeodomain protein, Cdx2/3 [25].
• We demonstrate here that the paired domain and homeodomain containing Pax-6 protein binds to three different sites in the promoter region of the L1 gene [26].
• Electrophoresis mobility shift assay and DNase I footprinting analysis show that at least three Pax6-binding sites are located in the 5'-flanking and 5'-non-coding regions of the rat c-maf gene [27].

Regulatory relationships of Pax-6

• Protein phosphatase-1 (PP1) is the major protein phosphatase modulating transcriptional activity of Pax6. De-phosphorylation of Pax6 by PP1 dramatically inhibit Pax6 induced expression of alpha-B crystallin [28] .
• Identification and characterization of a novel transcript down-regulated in Dlx1/Dlx2 and up-regulated in Pax6 mutant telencephalon [29].
• Pax6 promotes neuronal differentiation via transcriptional regulation of the Neurogenin2 (Ngn2) gene, although Pax6 expression appears in proliferating neuroepithelial cells before the onset of neurogenesis [30].
• Ectopic expression of Pax6 in the optic stalk under control of Pax2 promoter elements resulted in a shift of the optic cup/optic stalk boundary indicated by the presence of retinal pigmented cells on the optic stalk [31].
• We previously found that c-Maf, c-Jun, and Pax6 bind to and stimulate the c-maf gene [32].
• The overexpression of Pax4 in HIT-T15 cells dose dependently inhibited the basal transcriptional activity as well as Pax6-induced activity [24].
• We show that the expression of Trim11 is directly regulated by Pax6 in developing cortex in vivo [33].
• We show that Pax6 regulates the Wnt antagonist Sfrp2 in the lens, and that Sox2 expression is upregulated in the Pax6-deficient lenses [34].

Other interactions of Pax6

• This observation suggests that Vax1 may interfere negatively with the expression of Pax6 and Rx [35].
• These reciprocal alterations in cortical and striatal progenitor specification lead to the abnormal development of the cortex and striatum observed in Pax6 (small eye) and Gsh2 mutants, respectively [36].
• Lack of pigment epithelium specification was associated with an expansion of the prospective neural retina and optic stalk territories, as determined by the expression of Pax6, Six3 and Pax2 [37].
• Furthermore, we found an early restriction of Pax6 and Dlx1 expression into presumptive histogenetic fields that correlate with the formation of distinct forebrain structures and nuclei [16].
• These are always characterized by overlapping expression of Sox2/3 and Pax6 [38].

Analytical, diagnostic and therapeutic context of Pax6

• Pax6 binds this site through the paired domain in vitro as judged by electrophoretic mobility shift assay [13].
• METHODS: Double immunofluorescence staining was carried out for HNF-1alpha and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2) [39].
• Chromatin immunoprecipitations established in vivo interactions of Pax6 and c-Maf with the alphaA-crystallin promoter in lens cells [40].
• CONCLUSIONS: Together with functional analysis in a reporter gene assay and immunohistochemistry using Pax6 antibodies, it is suggested that the Pax6Aey11 and Pax6Aey18 alleles act through a loss of function, whereas ADD4802 represents a gain-of-function allele [41].
• The relative amount of Pax6-specific mRNA was determined by real-time PCR [41].

References