Abstract
Nkx2.2 and NeuroD1 are two critical regulators of pancreatic beta cell development. Nkx2.2 is a homeodomain transcription factor that is essential for islet cell type specification and mature beta cell function. NeuroD1 is a basic helix-loop-helix transcription factor that is critical for islet beta cell maturation and maintenance. Although both proteins influence beta cell development directly downstream of the endocrine progenitor factor, neurogenin3 (Ngn3), a connection between the two proteins in the regulation of beta cell fate and function has yet to be established. In this study, we demonstrate that Nkx2.2 transcriptional activity is required to facilitate the activation of NeuroD1 by Ngn3. Furthermore, Nkx2.2 is necessary to maintain high levels of NeuroD1 expression in developing mouse and zebrafish islets and in mature beta cells. Interestingly, Nkx2.2 regulates NeuroD1 through two independent promoter elements, one that is bound and activated directly by Nkx2.2 and one that appears to be regulated by Nkx2.2 through an indirect mechanism. Together, these findings suggest that Nkx2.2 coordinately activates NeuroD1 with Ngn3 within the endocrine progenitor cell and also plays a role in the maintenance of NeuroD1 expression to regulate beta cell function in the mature islet. Collectively, these findings further define the conserved regulatory networks involved in islet beta cell formation and function.
Highlights
The pancreas is an intricate organ composed of exocrine tissue that secretes digestive enzymes into pancreatic ducts, and the endocrine islets of Langerhans that produce the metabolic hormones insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin
These findings suggest that Nkx2.2 coordinately activates NeuroD1 with Ngn3 within the endocrine progenitor cell and plays a role in the maintenance of NeuroD1 expression to regulate  cell function in the mature islet
Because the reduction in NeuroD1 corresponds with the major wave of islet cell differentiation, we wished to determine whether the reduction of NeuroD1 expression was due to the loss of the ␣ and  cell populations that occurs in the Nkx2.2 null embryos
Summary
Nkx2.2 regulates NeuroD1 through two independent promoter elements, one that is bound and activated directly by Nkx2.2 and one that appears to be regulated by Nkx2.2 through an indirect mechanism Together, these findings suggest that Nkx2.2 coordinately activates NeuroD1 with Ngn within the endocrine progenitor cell and plays a role in the maintenance of NeuroD1 expression to regulate  cell function in the mature islet. We demonstrate that Nkx2.2 and Ngn can cooperate to activate a minimal NeuroD1 promoter element and the endogenous NeuroD1 gene These data suggest that, in addition to the complex functional roles of Nkx2.2 and NeuroD1 in regulating islet development and function, Nkx2.2 is a key component of the regulatory pathway that modulates NeuroD1 expression in the islet
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