Figure 4.

Mutations in the Nkx2.2 TN domain cause Arx misexpression in β cells and β-to-α-cell reprogramming. (A) Islet cell-specific transcription factor expression at E14.5 (n = 5). (B) By E18.5, β-cell factors are reduced, while α-cell factors are increased, reflecting the changes associated with these cell types (n = 5). (C) Nkx2.2^TNmut/TNmut mice exhibit a threefold to fourfold increase in Arx expression at E15.5, prior to the changes in glucagon expression and α-cell number (n = 5). (D,E) There are increased numbers of Arx⁺ cells and more Arx⁺/glucagon⁻ cells in Nkx2.2^TNmut/TNmut mice at E15.5, when the increase in Arx expression is first observed. (F–I) Between E15.5 and continuing through gestation, Arx is misexpressed in the β-cell population of Nkx2.2^TNmut/TNmut mice. (J,K) Using the β-cell-specific Ins:Cre and the Rosa26:tomato reporter, β-cell-derived glucagon-positive cells are frequently detected in Nkx2.2^TNmut/TNmut mice. (L) β-Cell-derived α cells express Arx (n = 3). (*) P < 0.05; (**) P < 0.01. Arrowheads in E indicate Arx⁺/glucagon⁻ cells. Arrowheads in G, I, and K indicate copositive cells. Arrowheads in L indicate triple-positive cells.