Model of Nkx6.1 function in endocrine precursor cells.

<p>(A) Expression of <i>Nkx6.1</i> results in allocation of precursors from all non-beta endocrine lineages to the beta cell lineage. Deletion of <i>Nkx6.1</i> in endocrine precursors has the opposite effect. When <i>Nkx6.1</i> is deleted in beta cells, beta cells convert into delta cells, but not into alpha or pancreatic polypeptide (PP)-producing cells. (B) Our study suggests that in endocrine precursors, Nkx6.1 and Isl1 compete for repression and activation, respectively, of the alpha cell fate determinant <i>Arx</i>. We also demonstrate that the expression of Pdx1 in endocrine precursors depends on Nkx6.1. In conjunction with previous studies, showing repression of Pdx1 and Nkx6.1 by Arx <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003274#pgen.1003274-Collombat4" target="_blank">[39]</a> and activation of Nkx6.1 by Pdx1 <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003274#pgen.1003274-Ahlgren1" target="_blank">[34]</a>, our data support a model whereby cross-repression between Arx and Nkx6.1 confers alpha <i>versus</i> beta cell precursor identity. In beta cell precursors, Nkx6.1 expression is reinforced by Pdx1, which is repressed by Arx in alpha cell precursors.</p>

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