c h a p t e r

30
Development of the Endocrine
Pancreas
Matthias Hebrok and Michael S. German

CHAPTER OUTLINE
PANCREAS MORPHOGENESIS,  517
EARLY ORGAN SPECIFICATION AND BUD
FORMATION, 518
Tissue Interaction and Signaling Pathways,  518
Induction of the Pancreatic Gene Expression
Program, 519
CELL TYPE DIFFERENTIATION,  522
Signaling Pathways,  522
Transcription Factors,  524
Islet Formation,  525
The Role of Pancreatic Development in Human
Diabetes, 526

KEY POINTS
• P  ancreatic organogenesis depends on permissive and instructive cues from surrounding
mesenchymal tissues.
• Embryonic signaling pathways guide all steps of pancreas organogenesis.
• Early pancreatic progenitor cells have the capacity to differentiate into all of the
pancreatic epithelial cell types.
• Notch signaling restricts expression of the pro-endocrine transcription factor Neurog3
and the generation of islet cells.
• Transcription factor cascades regulate specification and differentiation of pancreatic cell
types.  

The pancreas provides both the enzymes that digest the
food in the gut and the hormones that control utilization
of the nutrients supplied by that digested food. Two dis-
tinct components of the pancreas, the exocrine and endo-
crine compartments, accomplish these related tasks. The
ductal and acinar cells of the exocrine compartment com-
pose the majority of the organ, while the islets of Lang-
erhans of the endocrine portion are scattered throughout
the exocrine matrix.
During pancreatic development, a common pool of
progenitor cells in the early gut endoderm differentiates
into these distinct cell types. Positional and temporal cues
provided by extracellular signals direct sequential changes
in the gene expression program of individual cells, and
ultimately determine the phenotype of the differenti-
ated cells and the organization of the mature organ. Any
breakdown in the orchestration of this complex process
of growth, differentiation, migration, and organization
can damage the mature organ, and can cause diabetes by
impairing the function of the insulin-producing β cells.
An understanding of pancreatic development has pro-
vided us with new insights into the causes of diabetes and
new strategies for intervening in the disease.
PANCREAS MORPHOGENESIS
During gastrulation, mesendodermal cells that migrate
through the node region start to segregate to form dis-
tinct mesodermal and endodermal germ layers. Endoder-
mal cells aggregate to form a contiguous epithelium that
spans the whole length of the forming gastrointestinal
tract of the developing embryo. Digestive organs develop
along the antero-posterior and dorsal-ventral axes of this
sheet of cells in a precise and predetermined pattern.1-3
The pancreas forms from clumps of cells that bud from
the dorsal and ventral aspects of the gut endoderm near
the foregut/midgut junction4,5 (Fig. 30-1). Well before
any morphologic evidence of the pancreas becomes
apparent, interactions between the mesodermally-derived
notochord and the endodermal epithelium initiate dorsal
517