Disease relevance of Nkx2-2

• In addition, we show that mice homozygous for a null mutation of Nkx2.2 develop severe hyperglycemia and die shortly after birth [1].

High impact information on Nkx2-2

• 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 [2].
• These neuronal subtypes derive from distinct progenitor cell populations that express the homeodomain proteins Nkx2.2 or Pax6 in response to graded Shh signalling [2].
• Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling [2].
• The basic helix-loop-helix (bHLH) gene Ascl1 (also known as Mash1) is coexpressed with Nkx2-2 in the neuroepithelial domain of the hindbrain, which gives rise to 5-HT neurons [3].
• Nkx-2.2 transcripts are found in localized domains of the brain during mouse embryogenesis [4].

Biological context of Nkx2-2

• In vitro DNA-binding and transient transfection assays defined how Nkx2.2 affected insulin gene expression [5].
• Moreover, the DV factor Nkx2.2 enhances Hox-mediated transactivation via a derepression mechanism [6].
• Several conserved sites within Area I were important in Area I/Area II activation, with binding at bp -2614/-2609 specifically controlled by Nkx2.2, an insulin gene regulator that is required for terminal beta cell differentiation [7].
• We isolated and sequenced a 2026-bp murine Nkx-2.2 cDNA clone that contains an open reading frame encoding 273 amino acids (aa) [8].
• Lmx1b, Pet-1, and Nkx2.2 coordinately specify serotonergic neurotransmitter phenotype [9].

Anatomical context of Nkx2-2

• Remarkably, Nkx2-2 is ectopically activated in the sclerotome and limb buds of Pax1(Un-s) embryos, both of which normally express Pax1 [10].
• 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 [11].
• Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain [4].
• Within the pancreatic islet, the homeodomain protein Nkx2.2 is essential for the differentiation of all insulin-producing beta cells and a subset of glucagon-producing alpha cells (1) [12].
• Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor [13].

Physical interactions of Nkx2-2

• In developing neural tube, the basic helix-loop-helix (bHLH) transcription factor Olig2 interacts with the homeodomain transcription factor Nkx2.2 at two distinct stages [14].

Regulatory relationships of Nkx2-2

• Nkx2.2 was widely expressed in the ventricular zone of presumptive ZLI and also as a narrow band in the mantle zone [15].
• Olig3 was co-expressed with Nkx2.2 in the lateral margin of the p3 domain [16].
• At later times, a cooperative interaction is noted because Nkx2.2 promotes maturation of oligodendrocyte progenitor cells specified by expression of Olig2 [14].
• The homeodomain-containing transcription factor Nkx2.9 is expressed in the ventralmost neural progenitor domain of the neural tube together with the related protein Nkx2.2 during early mouse embryogenesis [17].

Other interactions of Nkx2-2

• Taken together, we propose that a combination of a loss-of-function mutation of Pax1 and a gain-of-function mutation of Nkx2-2 is the molecular basis of the Pax1(Un-s) mutation [10].
• Nkx2-9 expression overlaps with that of Nkx2-2 but is generally broader [18].
• In particular, the transcription factors (TFs) Olig2, Pax6, and Nkx2.2 have been shown to be important in the specification and/or maturation of the OG lineage [19].
• First, duct cells proliferated in the perfused segment, then cells co-expressing multiple islet hormones and transcription factors such as PDX-1, Nkx2.2, Isl1, and Pax6 were observed in duct cells, and newly formed islet-like cell clusters (ICCs) containing beta cells were recognized [20].
• Thus, Nkx2.2 has an essential role in interpreting graded Shh signals and selecting neuronal identity [2].

Analytical, diagnostic and therapeutic context of Nkx2-2

• In addition, another key islet-enriched transcription factor, Nkx2.2, was found to occupy this region using the chromatin immunoprecipitation assay [5].
• METHODS: Double immunofluorescence staining was carried out for HNF-1alpha and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2) [21].
• The number of cells expressing T1r3, gustducin, Mash1 and Nkx2.2 gradually decreased after denervation [22].

References