Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

Abstract

Lineage tracing studies have revealed that transcription factors play a cardinal role in pancreatic development, differentiation and function. Three transitions define pancreatic organogenesis, differentiation and maturation. In the primary transition, when pancreatic organogenesis is initiated, there is active proliferation of pancreatic progenitor cells. During the secondary transition, defined by differentiation, there is growth, branching, differentiation and pancreatic cell lineage allocation. The tertiary transition is characterized by differentiated pancreatic cells that undergo further remodeling, including apoptosis, replication and neogenesis thereby establishing a mature organ. Transcription factors function at multiple levels and may regulate one another and auto-regulate. The interaction between extrinsic signals from non-pancreatic tissues and intrinsic transcription factors form a complex gene regulatory network ultimately culminating in the different cell lineages and tissue types in the developing pancreas. Mutations in these transcription factors clinically manifest as subtypes of diabetes mellitus. Current treatment for diabetes is not curative and thus, developmental biologists and stem cell researchers are utilizing knowledge of normal pancreatic development to explore novel therapeutic alternatives. This review summarizes current knowledge of transcription factors involved in pancreatic development and β-cell differentiation in rodents.

Keywords: diabetes; islets; multipotent progenitor cell; pancreatic transitions.

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.