Loss of <i>Nkx6.1</i> in beta cells causes beta-to-delta cell conversion.

<p>Immunofluorescence staining of pancreata from <i>Nkx6.1^f/+;RIP-Cre;R26-YFP</i> and <i>Nkx6.1^f/−;RIP-Cre;R26-YFP</i> mice at 6 weeks of age shows Nkx6.1 (A) and insulin (B) expression in YFP⁺ cells of <i>Nkx6.1^f/+;RIP-Cre;R26-YFP</i> control mice, but loss of Nkx6.1 (F) and insulin (G) in YFP⁺ cells of <i>Nkx6.1^f/−;RIP-Cre;R26-YFP</i> mice. The insets display higher magnification images. YFP⁺ cells do not express glucagon (C, H) and rarely express pancreatic polypeptide (E, J; insets, arrowheads) in either genotype. While YFP⁺ cells are somatostatin⁻ in <i>Nkx6.1^f/+;RIP-Cre;R26-YFP</i> mice (D; insets, arrowheads), YFP-labeled cells are mostly somatostatin⁺ in <i>Nkx6.1^f/−;RIP-Cre;R26-YFP</i> mice (I; insets, arrowheads), suggesting beta-to-delta cell conversion. Arx expression is similar in both genotypes and absent from lineage-labeled YFP⁺ cells (K, M; inset, arrowhead), showing that loss of <i>Nkx6.1</i> in beta cells does not activate <i>Arx</i>. Pdx1⁺somatostatin⁺ cells are found in both genotypes (L, N; insets, arrowheads), but express YFP only in <i>Nkx6.1^f/−;RIP-Cre;R26-YFP</i> mice (L; inset, arrowhead). (O) Quantification of the percentage of hormone⁺YFP⁺ cells relative to all hormone⁺ cells for each islet cell type shows reduced numbers of insulin⁺YFP⁺ cells and increased numbers of in somatostatin⁺YFP⁺ cells in <i>Nkx6.1^f/−;RIP-Cre;R26-YFP</i> mice compared to <i>Nkx6.1^f/+;RIP-Cre;R26-YFP</i> mice at 6 weeks (n = 3). Wks, weeks; Ins, insulin; Glc, glucagon; PP, pancreatic polypeptide; Som, somatostatin; Horm, hormones. Scale bar = 50 µm. Error bars represent S.E.M; ***p<0.0001.