In the human embryo, the endocrine cells of the islets of Langerhans develop from epithelial pancreatic progenitor cells. Transcription factor neurogenin-3 is crucial for differentiation. Only with its help can insulin-producing beta cells develop. Neurogenin-3 gene mutations lead to diabetes. Researchers developed a technique to observe neurogenin-3 gene expression in human pancreatic cells. They discovered that even a weak expression enables beta cell formation to prevent the onset of diabetes.

The islets of Langerhans in the pancreas contain various endocrine cells that produce hormones essential for carbohydrate metabolism regulation. While beta cells produce the blood sugar-reducing hormone insulin, alpha cells, for example, produce its counterpart glucagon.

Neurogenin-3 Essential for Differentiation
During the pancreas development phase, transcription factor neurogenin-3 ensures the differentiation of these endocrine cells from the epithelial progenitor cells of the pancreas. For this reason, the highest neurogenin-3 concentration is found in the early phase of organogenesis with a significant reduction occurring before birth. The adult pancreas contains almost no neurogenin-3.

Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden and the DZD partner Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden, and the Novo Nordisk Foundation at the University of Copenhagen, studied how neurogenin-3 behaves in individual cells.

Weak Expression Is Sufficient
They developed 2- and 3-dimensional models using young human pancreatic cells in which they could localize neurogenin-3 using special markers. They discovered that the neurogenin-3 gene is expressed differently in the various pancreatic cells. Some cells display a strong expression and others only a weak expression. The researchers were surprised to find that despite the varying expression strengths, all pancreatic cells were endocrine active and producing hormones.

Apparently, even small amounts of neurogenin-3 are sufficient to trigger endocrine cell differentiation, e.g., beta cell development. According to the researchers, this is important as it explains why neurogenin-3 gene mutations with a small effect on activity do not result in the onset of diabetes in humans. Only mutations causing severe gene impairment lead to diabetes.

Beta Cell Development Requires Time
A further discovery was the fact that neurogenin-3 works slower in humans than in mice. For the researchers, this is evidence that the gene requires more time in humans to fulfill its tasks. Epithelial progenitor cells differentiating into beta or alpha cells take twice as long in humans as in rodents.

The cell culture systems the researchers developed help to better understand how cells develop organs in human embryos. The observation of neurogenin-3 in individual cells demonstrates how the activity of certain genes during embryonic development can lead to diabetes later in life.

Original publication:
Belin Selcen Beydag-Tasöz, Joyson Verner D’Costa, Lena Hersemann, Byung Ho Lee, Federica Luppino, Yung Hae Kim, Christoph Zechner, Anne Grapin-Botton. Integrating single-cell imaging and RNA sequencing datasets links differentiation and morphogenetic dynamics of human pancreatic endocrine progenitors. Developmental Cell 2023 Aug 16; doi: 10.1016/j.devcel.2023.07.019