The human pancreas is a vital organ responsible for both endocrine and exocrine functions, playing a crucial role in glucose metabolism and digestion. It originates from the foregut endoderm, with the dorsal and ventral buds forming and eventually fusing to develop into a mature pancreas. Key stages of pancreas development include specification, branching morphogenesis, and differentiation into endocrine and exocrine cell types (Jennings et al., 2015). Transcription factors play pivotal roles in pancreas development. Some of the key transcription factors include:
PDX1 (Pancreatic and Duodenal Homeobox 1): essential for early pancreas development and beta–cell differentiation (Offield et al., 1996); maintains progenitor cell populations and is involved in ductal and endocrine differentiation (Seymour & Sander, 2011),
NGN3 (Neurogenin 3): NGN3 marks endocrine progenitors and is crucial for islet cell development (Rukstalis & Habener, 2009).
NKX6.1: NKX6.1 Plays a key role in the maturation and function of beta cells (Sander & German, 1997)
RFX3: RFX3 is a critical transcription factor involved in the development and function of the endocrine pancreas. It plays a significant role in regulating gene expression necessary for the growth of cilia in pancreatic endocrine cells in mice, which is essential for maintaining the cellular composition of islets of Langerhans, insulin production, and glucose tolerance. RFX3 is also crucial for the differentiation and function of mature β–cells and directly regulates the β–cell promoter of the glucokinase gene, a key enzyme in glucose metabolism in the mouse pancreas ([Ait–Lounis et al., 2007] [Ait–Lounis et al., 2010]). While its role in mouse pancreatic development is less defined, its role in human pancreas development has never been explored before.
RFX6: RFX6 is a crucial transcription factor involved in the development and function of the pancreas, particularly in the differentiation of insulin–producing β–cells and regulation of insulin production. It is essential for the proper differentiation of endocrine cells, as seen in conditions like Mitchell–Riley Syndrome, where mutations in RFX6 lead to impaired pancreatic development (Trott et al., 2020).RFX6 also influences insulin synthesis by regulating genes involved in mRNA translation (Cheng et al., 2019)and mutations in this gene are linked to neonatal diabetes and other pancreatic dysfunctions (Concepcion et al., 2014), however, its role in human exocrine and endocrine pancreas has never been explored before.
Transcription factors belonging to the regulatory factor X (RFX) transcription factors are involved in regulating genes critical for ciliary development and function, playing roles in organogenesis and cellular differentiation across various tissues. The exact role of RFX3 in pancreas development is less understood but is thought to involve the regulation of gene expression patterns crucial for pancreatic differentiation (Chung et al., 2020). In this project, we are seeking to investigate the expression ofRFX3 and RFX6 in human fetal, neonatal, childhood and young adult pancreatic tissues to identify crucial novel factors of human pancreas development.
