Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development

Hormone Research Institute, University of California San Francisco, San Francisco, CA 94143-0534, USA.
Development (Impact Factor: 6.46). 01/2001; 127(24):5533-40.
Source: PubMed


Most insulin-producing beta-cells in the fetal mouse pancreas arise during the secondary transition, a wave of differentiation starting at embryonic day 13. Here, we show that disruption of homeobox gene Nkx6.1 in mice leads to loss of beta-cell precursors and blocks beta-cell neogenesis specifically during the secondary transition. In contrast, islet development in Nkx6. 1/Nkx2.2 double mutant embryos is identical to Nkx2.2 single mutant islet development: beta-cell precursors survive but fail to differentiate into beta-cells throughout development. Together, these experiments reveal two independently controlled pathways for beta-cell differentiation, and place Nkx6.1 downstream of Nkx2.2 in the major pathway of beta-cell differentiation.

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    • "Development of the ductal/endocrine lineages from MPCs is associated with loss of Ptf1a and maintenance of Nkx6-1 expression, whereas the downregulation of Nkx6-1 and sustained expression of Ptf1a are required for specification of the exocrine lineage (Schaffer et al., 2010). Expression of Nkx6-1 is required for development of the beta cell lineage from endocrine progenitors (Sander et al., 2000). "
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    • "A pancreatic progenitor cell is defined by coexpression of the transcription factors Pdx1, Nkx6.1, Nkx2.2, Ptf1a, and Sox9 in the embryonic pancreas epithelium, and the lack of one of these transcription factors can result in abnormal beta cell development (Gittes, 2009). For instance, pancreatic cells in homozygous Nkx6.1 mutant mice develop into NGN3-positive endocrine progenitors and insulin and glucagon co-expressing cells, but fail to form monohormonal insulin-expressing beta cells at embryonic day 18.5 (Sander et al, 2000). During mouse embryonic development, two waves of Ngn3 expression, initiated before and after Nkx6.1 expression, have a vastly different outcome on the phenotype of endocrine cells. "
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    • "The lung biomarker NAPSA is a well characterized proteinase expressed in type II pneumocytes [65] [66] [67], whose expression has high sensitivity and specificity for distinguishing primary lung adenocarcinoma from metastatic pulmonary lesions from other primaries [67]. The pancreas biomarker NKX6-1 is a transcriptional regulator that has been shown to play an important role in beta cell differentiation during pancreatic development [68] [69] [70] [71]. "
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