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Distinct expression patterns of splicing isoforms of mNumb in the endocrine lineage of developing pancreas

Authors

  • Tetsu Yoshida,

    1. Department of Physiology Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku Tokyo 160–8582 Japan
      Tel: 81-3-5363-3747, Fax: 81-3-3357-5445
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  • Akinori Tokunaga,

    1. Department of Physiology Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku Tokyo 160–8582 Japan
      Tel: 81-3-5363-3747, Fax: 81-3-3357-5445
    2. Core Research for Evolutional Science and Technology (CREST) Japan Science and Technology Corporation Saitama 332-0012 Japan
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  • Keiko Nakao,

    1. Department of Physiology Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku Tokyo 160–8582 Japan
      Tel: 81-3-5363-3747, Fax: 81-3-3357-5445
    2. Core Research for Evolutional Science and Technology (CREST) Japan Science and Technology Corporation Saitama 332-0012 Japan
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  • Hideyuki Okano

    Corresponding author
    1. Department of Physiology Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku Tokyo 160–8582 Japan
      Tel: 81-3-5363-3747, Fax: 81-3-3357-5445
    2. Core Research for Evolutional Science and Technology (CREST) Japan Science and Technology Corporation Saitama 332-0012 Japan
      ✉ e-mail: hidokano@sc.itc.keio.ac.jp
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✉ e-mail: hidokano@sc.itc.keio.ac.jp

Abstract

Abstract The pancreas is composed of three tissues: endocrine, exocrine, and duct. The endocrine/exocrine lineages diverge from the ductal lineage before E12.5 in mice, and then further separate into endocrine and exocrine precursors. These processes are regulated by differential activation of Notch1-mediated signaling, which is required to repress the expression of the pro-endocrine gene neurogenin3 (ngn3) in the exocrine lineage. Mammalian Numb (mNumb) is an ortholog of Drosophila Numb (dNumb), which is likely to be an intracellular inhibitor of Notch signaling, and has four splicing isoforms: PTBS-PRRS, PTBL-PRRS, PTBS-PRRL, and PTBL-PRRL. Here we developed an anti-PRRL antibody, which recognizes only the PRRL forms of mNumb. We then performed immunohistochemical analyses using anti-PRRL together with anti-pan Numb, which recognizes all the isoforms of mNumb, antibodies that determine the spatio-temporal expression pattern of mNumb in the mouse fetal pancreas. mNumb PRRS and PRRL were first expressed in identical cells in the early stage of pancreatic development (i.e., E10.5), but gradually became biased. At the stage of endocrine and exocrine divergence, mNumb PRRS continued to be expressed in endocrine lineage cells, whereas PRRL was down-regulated during endocrine differentiation. Even after the endocrine/exocrine divergence, notch1 expression was sustained in endocrine lineage, where ngn3 was expressed. These results agree with the notion that mNumb PRRS has an inhibitory effect on Notch signaling, indicating its poten-tial roles in the differentiation of pancreatic endocrine lineage. In addition, islet cells, which are produced from ductal tissue, were immunostained by the anti-panNb antibody. Our present results will contribute to the understanding of the mechanisms of islet development from ductal tissue.

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