Abstract
The basic helix-loop-helix transcription factor, NEUROG3, is critical in causing endocrine commitment from a progenitor cell population in the developing pancreas. In human, NEUROG3 has been detected from 8 weeks post-conception (wpc). However, the profile of its production and when it ceases to be detected is unknown. In this study we have defined the profile of NEUROG3 detection in the developing pancreas to give insight into when NEUROG3-dependent endocrine commitment is possible in the human fetus. Immunohistochemistry allowed counting of cells with positively stained nuclei from 7 wpc through to term. mRNA was also isolated from sections of human fetal pancreas and NEUROG3 transcription analyzed by quantitative reverse transcription and polymerase chain reaction. NEUROG3 was detected as expected at 8 wpc. The number of NEUROG3-positive cells increased to peak levels between 10 wpc and 14 wpc. It declined at and after 18 wpc such that it was not detected in human fetal pancreas at 35–41 wpc. Analysis of NEUROG3 transcription corroborated this profile by demonstrating very low levels of transcript at 35–41 wpc, more than 10-fold lower than levels at 12–16 wpc. These data define the appearance, peak and subsequent disappearance of the critical transcription factor, NEUROG3, in human fetal pancreas for the first time. By inference, the window for pancreatic endocrine differentiation via NEUROG3 action opens at 8 wpc and closes between 21 and 35 wpc.
Highlights
Understanding b-cell differentiation is central to appreciating how b-cell mass is generated in preparation for post-natal life
Studies predominantly in mouse have demonstrated conclusively that the basic helix-loop-helix factor, Neurogenin 3 (NEUROG3, known as NGN3), is required for endocrine commitment.[3,4]. This occurs in a population of progenitor cells themselves regulated by key transcription factors, such as Sex determining region Y-box 9 (SOX9) and pancreas and duodenal homeobox 1 (PDX1).[3,4]
In early human embryos there is no first phase of NEUROG3 but the transcription factor becomes progressively detected immediately after the embryonic period at »8 weeks post-conception timed with the appearance of the first fetal b-cells.[8]
Summary
Understanding b-cell differentiation is central to appreciating how b-cell mass is generated in preparation for post-natal life. Whether compared to either total pancreatic cells or the SOX9-positive cell population, the profile of NEUROG3 detection was very similar (Fig. 2A-B).
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