Overview of transcription factors governing pancreas development and β-cell neogenesis and phenotypes of respective mouse mutants

FactorTypeOnset*Expression/role(s)Pancreatic phenotype of mouse mutant(s)
Bapx1 aka Nkx3.2HD≤e9.5Acts in splenic mesenchyme to correctly position and partition developing d.p. and spleen (16)Bapx1−/−: d.p. undergoes metaplastic transformation into intestinal-like tissue because of prolonged interaction with splenic mesenchyme (16)
HhexHDe7.0Directs v.p. specification (17)Hex−/−: v.p. not specified: reduced proliferation of bipotential ventral foregut endoderm cells does not position them beyond prohepatic influence of the cardiac mesoderm to permit pancreatic induction (17)
Sox17HMG box≤e5.5Expressed throughout endoderm postgastrulation (113); assigns ventral pancreatic vs. extrahepatobiliary fate in ventral foregut progenitor cells (26)Foxa3-Cre; Sox17fl/fl: loss of biliary primordium (gall bladder and cystic duct); ectopic pancreas in common duct (26). Pdx1tTa/+; tetO-Sox17: d.p. and v.p. agenesis (26)
Foxa2 aka Hnf3βwinged helix≤e5.5Expressed throughout the early pancreatic endoderm; restricted to acinar and endocrine cells by late gestation (30;114–115); required for islet function (32;118)Foxa2−/−: embryonic lethal; absence of foregut endoderm (116;117)Foxa3-Cre; Foxa2fl/fl: hypoglycemia; hypoglucagonemia; loss of α-cells (32). Ins-Cre; Foxa2fl/fl: hyperinsulinemic hypoglycemia (118)
Hnf6 aka OC1HD≤e9.0Expressed in MPCs and becomes restricted to acini and ducts (31;119;120); required for endocrine differentiation (33)Hnf6−/−: d.p. and v.p. hypoplastic (persists postnatally) because of delayed Pdx1 expression; loss of Ngn3+ endocrine progenitors; reduced endocrine cell numbers (31;33)
Hb9 (from Hlxb9 gene)HD≤e8.0Foregut and midgut endoderm, then dorsal and ventral pancreatic buds; becomes β-cell–restricted (27;28). Required for dorsal pancreas development and β-cell terminal differentiation (27;28)Hlxb9−/−: d.p. agenesis (27;28); reduced numbers of β-cells in ventral pancreas, which also showed decreased Glut2 (27;28) and Nkx6.1 expression (27); increased numbers of δ-cells (28)
Hnf1β aka Tcf2 aka vHnf1HD≤e8.5Expressed in MPCs and progenitor cords (34;121); required for growth of pancreatic buds (34)Tcf2−/−: v.p. undetectable; d.p. growth-arrested ≥e10.5 and lost by e13.5 because of reduced proliferation (34)
Isl1HD≤e9.0Expressed in dorsal pancreatic mesenchyme and in endocrine cells (42). Required for pancreatic epithelial growth and endocrine differentiation (42). Required for the maturation, proliferation and survival of second wave endocrine cells (110)Isl1−/−: absence of dorsal pancreatic mesenchyme and so defective exocrine differentiation; complete abrogation of endocrine development because of function in epithelial cells (42) Pdx1-Crelate; Isl1fl/fl: hyperglycemia; islet hypoplasia; reduced numbers of Pax6+ late endocrine progenitors; decreased proliferation and increased apoptosis of endocrine cells; impaired endocrine cell maturation (110)
Pdx1HDe8.5–e8.75Expressed in MPCs (37), progenitor cords then β-cells (18–20); required for growth of pancreatic buds (19;20;24)Pdx1−/−: v.p. agenesis; d.p. growth-arrested ≥e10.5 (19;20;24)Pdx1+/−: glucose intolerance; impaired GSIS; increased susceptibility to β-cell apoptosis (122)
Ptf1abHLHe8.5–e8.75Expressed in MPCs (21), then acinar cells (22); promotes ventral pancreatic fate (21); governs acinar program (21;23;62)Ptf1a−/−: v.p. agenesis (cells diverted to intestinal and CBD fate); d.p. growth-arrested ≥e10.5; in d.p., endocrine cells present but acinar cells lost (21;23;24)
Hes1bHLHMaintains MPCs by preventing cell cycle exit and differentiation (49–51) by repressing Ngn3 (53) and p57 (49), respectivelyHes1−/−: d.p. and v.p. hypoplasia because of MPC pool depletion through precocious differentiation (49–51); acinar dysgenesis (50); ectopic pancreas in distal stomach, duodenum, and CBD (123)
Sox9HMG box≤e9.0Expressed in MPCs and progenitor cords (55;63;124); required for growth of pancreatic buds (55) and generation of Ngn3+ endocrine progenitors (63)Pdx1-Creearly; Sox9fl/fl: d.p. and v.p. hypoplasia because of MPC pool depletion; increased apoptosis, reduced proliferation, and precocious differentiation (55) Pdx1-Creearly; Sox9fl/+: islet hypoplasia because of reduced numbers of Ngn3+ endocrine progenitor cells (63)
Nkx6.1HD≤e9.0Expressed in MPCs, Ngn3+ endocrine progenitors, then β-cells (62;93). Specifies MPCs toward an endocrine/ductal fate (62). Required for β-cell differentiation (93)Nkx6.1−/−: 85% reduction in β-cell numbers (93); additional loss of α-cells in Nkx6.1−/−; Nkx6.2−/− mutants (125). Nkx6.1−/−: ectopic trunk Ptf1a expression and loss of Ngn3+ cells; both more acute in Nkx6.1−/−; Nkx6.2−/− mice (62)
Nkx6.2HD≤e10.5Expressed in MPCs, then by e15.5, only in some glucagon+ cells and acinar cells (125). Functionally equivalent to Nkx6.1 (126)Nkx6.2−/−: no obvious pancreatic phenotype (125)
Ngn3bHLH≤e9.5Endocrine progenitor cell marker then later expressed in islet cells (51;74;75); cell-autonomously induces commitment to endocrine lineage (51); required for formation of all endocrine cells (74). Maintains endocrine function (75)Ngn3−/−: absence of all pancreatic endocrine and intestinal enteroendocrine cells (74;78;79); acinar dysmorphogenesis (74) Ins2-Cre; Ngn3fl/-: hyperglycemia; impaired β-cell maturation (75)
Ia1 aka Insm1Zinc finger≤e9.5Expressed in endocrine progenitors and some differentiated endocrine cells in Ngn3-dependent manner (83;84)Ia1−/−: impaired differentiation of pancreatic α- and β-cells and gut enteroendocrine cells (84)
Neuro D1 aka Beta2bHLH≤e9.5Expressed in differentiating and mature endocrine cells (83;86). Required for normal islet formation (86) and for the acquisition and maintenance of the fully functional, glucose-responsive β-cell phenotype (111)NeuroD1−/−: islet hypoplasia and dysgenesis, endocrine apoptosis and aberrant differentiation; disrupted enteroendocrine differentiation (86). RIP-Cre (or Pdx1-CreERT); NeuroD1fl/-: hyperglycemia; reduced pancreatic insulin (ins1 mRNA reduced); β-cell immaturity (111)
Nkx2.2HD≤e9.5Expressed in MPCs, then α-, β-, and PP-cells (87). Required for β- and α-cell development (87;89)Nkx2.2−/−: β-cell loss and α- and PP-cell reduction; ε-cell numbers expanded (87;89)
Pax4HD≤e9.5Expressed in endocrine progenitors then becomes restricted to β- and δ-cells (88); Ngn3-dependent expression. Promotes allocation to β-cell fate (88–90)Pax4−/−: β- and δ-cell loss; ε- and α-cell numbers expanded (88–90)
ArxHD≤e9.5Expressed in α- and PP-cells in Ngn3-dependent manner (94;95); promotes acquisition of α- and PP-cell fate; represses β- and δ-cell fate (94)Arx−/−: α-cell loss; β- and δ-cell numbers expanded (94)
Rfx6Winged helix≤e9.0Expressed in endocrine progenitors and all islet cell types in Ngn3-dependent manner (97;98). Restricts expression of Nkx6.1 (97)Rfx6−/−: small bowel obstruction; incompletely penetrant pancreatic hypoplasia; loss of all hormone-expressing (except PP-) cells; partial activation of endocrine program (97)
MafABasic leucine zipper≤e13.5β-Cell–specific activator of insulin gene transcription (104 [review]); exclusive expression in insulin+ cells from e13.5 onwards (105;107)MafA−/−: no obvious pancreatic developmental phenotype; development of glucose intolerance postnatally (108)
MafBBasic leucine zipper≤e10.5Expressed in insulin+ and glucagon+ cells by e12.5; restricted to α-cells postnatally (106;107). Regulates transcription of key factors required for α- and β-cell maturation (109)MafB−/−: α- and β-cell numbers reduced throughout pancreas development while total endocrine cell numbers unaffected; insulin+ cell neogenesis delayed (109)
  • *Onset of expression in or adjacent to the prepancreatic or pancreatic domain. aka, also known as; d.p., dorsal pancreas; GSIS, glucose-stimulated insulin secretion; v.p., ventral pancreas.