Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

Figures & data

Table 1. tiTranscription factors regulating the pancreatic transitions.

Transcription factor	Primary (e8.5–12.5) transition	Reference
Role
Hb9	Required for dorsal pancreatic development	^56-57
Isl1	Involved in dorsal pancreatic mesenchyme development	^26
Hnf1β	Required for ventral pancreatic bud development	^66
Hnf3β/Foxa2	Expressed and maintained in the definitive endoderm	^79-80
Hnf6/Onecut1	Required for ventral pancreatic bud development	^65,68
Sox17	Regulates endoderm development	^81,82
Pdx1	Involved in the development of pancreatic buds and expressed in pancreatic progenitor population	^27,85,89
Ptf1a	Required for the development of the pancreatic buds and expressed in pancreatic progenitors	^28,99
Sox9	Expressed in pancreatic progenitors and maintains Notch signaling	^114
Gata4	Present in foregut endoderm, dorsal and ventral epithelium and later restricted to acinar cells	^127-128
Gata6	Present in foregut endoderm, dorsal and ventral epithelium and later restricted to endocrine and ductal cells	^127-128
Secondary (e12.5–16.5) and tertiary (e16.5-postnatal) transitions
Ngn3	Expressed in all endocrine progenitor cells	^131
Hes1	Triggers differentiation of pancreatic precursors toward non-endocrine cell fate	^70,136-137
Hnf6	Involved in duct cell differentiation and later maintained in duct cells	^65,68
Sox9	Involved in differentiation of pancreatic precursors to their respective lineages and later confined to ductal cells	^114-115
Pdx1	Involved in differentiation of endocrine progenitors and later expressed in β- and δ-cells; regulates β-cell function	^86-88
Ptf1a	Controls exocrine cell differentiation	^99
NeuroD1	Involved in the development and maturation of β-cells	^145
Rfx3	Required for islet cell development	^159
Rfx6	Required for islet cell development	^146
Isl1	Involved in dorsal exocrine and all endocrine cell development	^26,163
Arx	Expressed in endocrine progenitors, required for α- and PP-cell maturation	^181-182
Pax4	Expressed in endocrine progenitors, required for β- and δ-cell maturation	^186
Pax6	Expressed in endocrine cells and required for differentiation of α- and β-cells	^195
Nkx2.2	Expressed in endocrine progenitors and later confined to α-, β- and PP-cells; maintains β-cell function	^40,167
Nkx6.1	Expressed in Ngn3^+ endocrine precursors, later restricted to β-cells; required for β-cell differentiation	^175
MafB	Expressed in α- and β-cells, later confined to α-cells; required for development and terminal differentiation of β-cells	^210
MafA	Switch from MafB to MafA expression critical for β-cell maturation; required for normal embryonic insulin concentrations	^219-221
Glis3	Involved in β-cell development and insulin expression	^200-202

Figure 1. Transcription factors regulating pancreatic organogenesis, differentiation and maturation. Key pancreatic transcription factors, in concert with extrinsic signals from non-pancreatic organs, form an intricate regulatory network orchestrating pancreatic development. Pancreatic development is classified into 3 different stages: the primary, secondary and tertiary transitions. In mice, at e7.5 prior to the primary transition (e8.5–12.5), the formation of the pancreatic endoderm is initiated and pre-differentiated cells shift to proto-differentiated cells. Several transcription factors involved in early pancreatic development are also observed in later transitions. During the secondary transition (e12.5–16.5), proto-differentiated tissue yield fully differentiated cells. A critical regulatory system, involving Sox9, Notch signaling, Hes1 and Ngn3, is required for exocrine and endocrine progenitor cell differentiation. Subsequently, endocrine precursors are further differentiated via the antagonistic relationship between Pax4 and Arx. There are several dynamic interrelationships between transcription factors that lead to cell lineage decisions. Finally, during the tertiary transition (e16.5-postnatal), differentiated endocrine cells organize into cell aggregates to undergo further maturation postnatally. These specialized islet cells are plastic during early neonatal life; throughout life they are dynamic and can compensate in response to fluctuating metabolic demand; and with aging their proliferative and compensatory abilities diminish. These specific transcription factors are thus integral for pancreatic development, cellular differentiation and maturation into a functional organ.

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