Table 1 NKX6.1 expression and function during pancreas development in rodents and humans
Developmental stage/specific role | NKX6.1 expression and function | |
|---|---|---|
Rodents | Human | |
Expression in the pancreatic epithelium | - At E9.5, Nkx6.1 starts to be expressed in the pancreatic epithelium [28]. | - At G6.5w, NKX6.1 is first detected in dorsal buds [19]. |
- At E10.5, Nkx6.1 and Ptf1a are co-expressed in the majority of MPCs. | ||
- At E12.5, Nkx6.1 becomes exclusively confined in the trunk cells [28]. | - At ~G7w, the NKX6.1 is co-localized with the early acinar marker, GATA4 in the MPCs giving rise to acinar cells [19]. | |
- At ~G9w, NKX6.1 is detected in the tip cells before losing the expression a week later and becoming confined to the trunk area [19]. | ||
Expression in endocrine cells | - At E13.5, the appearance of the first Ins+ cells co-expressing Nkx6.1 [30]. | - In adult islets, the NKX6.1 is exclusively expressed in β cells [19]. |
- Ngn3 and Nkx6.1 co-expression at the endocrine progenitor stage is crucial for their commitment to β cell lineage [38]. | ||
- hESC-derived β cells arise from NKX6.1+ endocrine progenitors co-expressing NGN3 [33, 72,73,74]. | ||
- Nkx6.1 is exclusively expressed in mature β cells [30]. | ||
Expression in ductal cells | - Ductal cells mature from NKX6.1+ progenitors [41]. | - hESC-derived MPCs expressing NKX6.1+/SOX9++ represent ductal progenitors [24]. |
Role in β cell maturation and function | - Nkx6.1 directly controls the expression of β cells and insulin processing genes (Glut2, G6pc2, Pcx, Ero1lb, and Slc30a8) and controls the expression of TFs of β cell development, including Rfx6, MafA, Mnx1, and Tle3 [46]. | - In human islets, NKX6.1 overexpression does not improve on GSIS [54]. |
- hPSC-derived MPCs co-expressing PDX1 and NKX6.1 differentiate into functional β cells in vitro and in vivo [18, 33, 72,73,74]. | ||
- hPSC-derived pancreatic progenitors lacking PDX1 (PDX1−/NKX6.1+) generate mature β cells [75]. | ||
Role in β cell identity | - Nkx6.1 suppresses Ngn3 in adult β cells to their main identity and prevents their conversion into Sst-expressing δ cells [45]. | - NKX6.1 expression does not co-localize with SST, PP, or amylase during early or adult pancreas development [19]. |
- Nkx6.1 suppresses Gcg expression by targeting PAX6 [52]. | ||
- ARX and GCG genes are completely absent in hiPSC-derived β cells that express NKX6.1 [76]. | ||
Role in β cell proliferation | - Nkx6.1 controls the expression of Nr4a1, Nr4a3, and c-Fos, which are crucial for β cell proliferation [59, 60]. | - In human islets, overexpression of NKX6.1 enhances β cell proliferation [54]. |
- Nkx6.1 controls the expression of AURKA, which suppresses p53 [63]. | ||
- Nkx6.1 controls the expression of Glut2 and Glp1r, which are crucial for β cell proliferation [46]. | ||