FGF-signalling in the differentiation of mouse ES cells towards ...

Figure 1-3: Regional expression of transcription factors in the endoderm. Although their expression is here mappedin the chicken embryo, their homologs are expressed in a similar regional manner in the mouse. The transcriptionfactors shown on the left, mostly homeobox genes, are mapped to specific regions of the endoderm, as shown on theright.. These genes are not only regionally expressed in already shaped organs (as shown in the E4 chicken gut tube),but also in the endodermal sheet prior to organ formation, with stable expression domains that can be used as markersof presumptive regions. The top left pink triangle shows Hex expression in the thyroid. The bottom left triangle refersto pancreas bud and the bottom right triangle to liver bud. BA1–4, branchial arches 1–4; Chicken CdxA = mouseCdx2. Modified from (Grapin-Botton and Melton 2000).Pancreas and β cell formationPdx1 is expressed in the region of the gut tube where the pancreatic primordia start to bud aroundE8.75 (Figure 1-2C) and all pancreatic cell types derive from this PDX1-positive (PDX1 +hereafter) domain (Jonsson et al. 1994). The ventral and dorsal buds form from the midline andlateral areas of the PDX1 + gut, respectively, then grow and branch extensively before fusing tobecome one pancreas by E12.5 (Figure 1-2D; (Jorgensen et al. 2007)). The ventral bud precedesthe dorsal bud and expresses the Homeobox transcription factor HB9 (Hlxb9) and Pdx1concomitantly whereas the dorsal bud expresses these sequentially and exclude sonic hedgehog(SHH)-signalling (Hebrok et al. 1998). SHH repression allows pancreatic budding in this regionand is determined by the underlying notochord. Expression of the Pancreas-specific transcriptionfactor 1a subunit (Ptf1a; or p48) is limited to the dorsal and ventral epithelium and is coexpressedwith Pdx1. The ventral pancreas develops in close association with the adjacent hepaticand bile duct endoderm and restriction of the ventral pancreas is dependent on TGFβ (SMAD2/3),BMP (SMAD1/5/8) and FGF-signalling from the cardiac mesoderm (Deutsch et al. 2001; Rossi etal. 2001). TGFβ-signalling is stable whereas FGF and BMP-signalling are dynamic and canchange within a few somite stages (Wandzioch and Zaret 2009). The dorsal pancreas does notshow active BMP or FGF-signalling at this stage, but rather is specified by dynamic TGFβ-10