Tissue-tissue interactions between the cardiogenic mesoderm and endoderm induce liver development while suppressing the pancreas. The homeoprotein Pdx1 promotes pancreatic development, but is repressed by Shh signaling from the surrounding mesoderm. The liver bud develops from the foregut endoderm and expands into the surrounding mesenchyme, forming connections to surrounding structures. Pancreatic development begins with dorsal and ventral buds expressing Pdx1, which later fuse to form the pancreas.

1. Development of liver and pancreas
Semmelweis University,
Department of Anatomy, Histology and Embryology
Dr. Kocsis Katalin
2018.04.19.

2. Development of the foregut

4. mellső végtag caudális határa
atlas

5. Hox gene expression boundaries in the endoderm and mesoderm during early chick gut development. Specific
combinations of homeobox gene expression can be mapped to specific regions of the gastrointestinal tract, with
some combinations demarcating the position of sphincters and organs. The regional expression patterns of mouse
homologs are similar.

7. Figure 14-5 Signals and transcription factors important in establishing regional differences in the early developing gastrointestinal tract. The top drawing
represents an early mammalian embryo shortly after the initiation of embryonic folding, with areas enlarged below showing some of the signaling events
involved in liver, pancreas, and hindgut specification. After initiation of cranial body folding, the endoderm of the ventral foregut is situated adjacent to the caudal
cardiogenic mesoderm and septum transversum. Tissue-tissue interactions between the cardiogenic mesoderm and the endoderm, mediated by Fgf and Bmp
signals, induce hepatocytic markers within the endoderm (e.g., Albumin and Alpha fetoprotein) while suppressing pancreatic development by upregulating Shh
expression. The homeoprotein pancreatic/duodenal marker, Pdx1, promotes pancreatic development. However, in the presence of Shh, pancreatic development
is repressed. Much of the endoderm expresses Shh, but it is repressed by notochordal release of Fgfs and Activin B in the future pancreatic region. Shh
expression within the hindgut endoderm induces Bmp4 and Hoxd13 expression within the caudal mesoderm. Shh/Bmp4 are only capable of inducing Hoxd13
expression in the caudal gut, possibly due to the caudal restriction of Cdx2 expression established during gastrulation. Hoxd13 instills a caudal identity to the
hindgut. Alb, Albumin, Afp, Alpha fetoprotein; Ipf1, insulin promoter factor 1.

8. 26 D
20 D
24 D
26 D
ductus
omphalo-
entericus
aortic
arch
foregut
aorta a. vitellina
hindgut
a. umbi-
licalis
entoderm
yolk sac
midgut
allantois
foregut
yolk sac
yolk sac
hindgut
ductus
omphalo-
entericus
szik-
hólyag

12. membrana cloacalis
cloaca hindgut
allantois
body stalk
yolk sac
ductus omphalo-
entericus
cardiogenic
area
esophagus
stomach
pharyngeal gut
ductus
thyreoglossus
membrana
buccopharyngea
lung
midgut
foregut
flexura
duodenojejunalis
flexura coli
sinistra
cecum

14. Liver development

15. Figure 14-9 Development of the liver, gallbladder, pancreas, and their duct systems from endodermal diverticula of the duodenum. The liver bud sprouts during
the 4th week and expands in the ventral (anterior) mesentery. The cystic diverticulum and ventral pancreatic bud also grow into the ventral mesentery, whereas
the dorsal pancreatic bud grows into the dorsal mesentery. During the 5th week, the ventral pancreatic bud migrates around the posterior side (former right side)
of the duodenum to fuse with the dorsal pancreatic bud. The main duct of the ventral bud ultimately becomes the major pancreatic duct, which drains the entire
pancreas.

16. Figure 14-14 Formation of the liver and associated membranes. As the liver bud grows into the ventral mesentery,
its expanding crown makes direct contact with the developing diaphragm. The ventral mesentery that encloses the
growing liver bud differentiates into the visceral peritoneum of the liver, which is reflected onto the diaphragm. This
zone of reflection, which encircles the area where the liver directly contacts the diaphragm (the bare area),
becomes the coronary ligament. The remnant of ventral mesentery connecting the liver with the anterior body wall
becomes the falciform ligament, whereas the ventral mesentery between the liver and lesser curvature of the
stomach forms the lesser omentum.

18. Tissue-tissue interactions between the cardiogenic mesoderm and the endoderm, mediated by Fgf
and Bmp signals, induce hepatocytic markers within the endoderm (e.g., Albumin and Alpha
fetoprotein) while suppressing pancreatic development by upregulating Shh expression.
induction (SHH, cardiogenic mesoderm):
BMP (2, 4, 7), FGF (1, 2, 8),
Wnt, GATA4, Hnf3, C/EBP
Hex (hematopoietically expressed
homeobox) essential for the hepatocyte
differentiation
cell differentiation, mesoderm, endothel
migration:
Notched / Jagged1,(Alagille syndrome)
Vegf, BMP, FGF
adult liver functions (albumin, alfa
fetoprotein synthesis):
Hnf (hepatic nuclear factor family)
C/EBP, Egf, Hgf, Tgf

19. Sites of hematopoiesis in the human embryo. The graph highlights the relative importance of the
various sites of hematopoiesis. AGM, aorta/genital ridge/mesonephros region. (Based on Carlson
B: Patten's foundations of embryology, ed 6, New York, 1996, McGraw-Hill).

21. regeneration capacity of the liver cells
Figure 18.29.
Kinetics of DNA synthesis in the four major cell types of the mammalian
liver. It is possible that, since the hepatocytes respond fastest, they are
secreting paracrine factors that induce DNA replication in the other cells.

22. Pancreas
development

24. Figure 14-9 Development of the liver, gallbladder, pancreas, and their duct systems from endodermal diverticula of the duodenum. The liver bud sprouts during
the 4th week and expands in the ventral (anterior) mesentery. The cystic diverticulum and ventral pancreatic bud also grow into the ventral mesentery, whereas
the dorsal pancreatic bud grows into the dorsal mesentery. During the 5th week, the ventral pancreatic bud migrates around the posterior side (former right side)
of the duodenum to fuse with the dorsal pancreatic bud. The main duct of the ventral bud ultimately becomes the major pancreatic duct, which drains the entire
pancreas.

25. dorsal pancreas bud (corpus és
cauda pancreatis)
duodenum
pancreas ventrale dexter (:
caput pancreatis és proc.
uncinatus)
pancreas ventrale
sinister (regrediated)
liver bud

26. Pancreas buds induction: aorta, Pdx1 homeobox genes
• Pancreas / blood vessel

29. Figure 14-10 Initiation of pancreatic development in a day 10 mouse embryo. Pancreatic
development begins with the formation of endodermal buds projecting into the splanchnic
mesoderm near the stomach-duodenal border. Pdx1 is expressed (seen here by immunostaining in
green) in both the dorsal and ventral pancreatic bud endoderm. Glucagon-positive cells are also
detected at this early stage (cells in red) within the pancreatic endodermal buds.

30. Tissue-tissue interactions between the cardiogenic mesoderm and the endoderm, mediated by Fgf
and Bmp signals, induce hepatocytic markers within the endoderm (e.g., Albumin and Alpha
fetoprotein) while suppressing pancreatic development by upregulating Shh expression. The
homeoprotein pancreatic/duodenal marker, Pdx1, promotes pancreatic development. However, in
the presence of Shh, pancreatic development is repressed.

33. Fig.8. Model of beta-cell development. In beta-cell precursors, Ngn3 induces the
expression of Pax4; these cells also express Nkx2.2 and Nkx6.1, and shortly
thereafter, they express Islet1 and Pax6. The parallel activities of Pax4 and Nkx2.2
enable the program of beta-cell differentiation, and as a result, the level of
Pdx1 increases; the expression of HB9 is induced; and the synthesis of insulin
ensues. In fully mature beta cells, the activity of Pax4 is no longer required.

34. Irodalom
•Scott F. Gilbert: Developmental Biology (7th edition, Sinauer
Associates, 2003)
•Gary Schoenwolf: Larsen's: Human Embryology (4th edition,
Elsevier, 2009)
•Thomas W. Sadler: Langman's Medical Embryology (10th
edition, Lippincott Williams and Wilkins, Philadelphia, 2006)
•Carlson BM. Human Embryology and Developmental Biology
(Mosby, Philadelphia, 2004)