Liver Bud Growth
| StemBook |
| This research on liver development was published on StemBook by Dr. Zorn and his laboratory. |
| Table of Contents |
|
|
Figure 9. Liver bud growth. |
| The schematics depict the liver bud at e9.5 when the hepatoblasts are invading the STM and at e10.5, when the hepatoblasts have grown into the liver bud in characteristic “chords” that are intermingled with the hepatic mesenchyme. At e10.5 haematopoietic cells also colonize the liver bud. Some the genes involved in liver bud growth are indicated. |
Mesenchymal Signals | Hepatoblast Proliferation and Survival
Between e9.5 to e15 the liver bud undergoes tremendous growth and becomes the major site of fetal haematopoiesis. This growth is regulated by paracrine signals from hepatic mesenchyme, as well as by genes that act intrinsically in the hepatoblasts. Mutations in many of these genes result in a similar embryonic lethality between e10-e16 due to impaired hepatoblast proliferation and/or increased cell death, which often causes severe anemia because the defective liver cannot support fetal haematopoiesis.
Mesenchymal Signals
The STM and hepatic mesenchyme (e.g. stellate cells) secrete a variety of growth factors including; FGF, BMP, HGF, Wnt, TGFβ and RA that promote hepatoblast migration, proliferation, and survival (see Fig. 9).
In addition to their earlier role in hepatic specification, FGF (via PI3 kinase) and BMP signaling also promote liver bud growth (Berg et al., 2007; Calmont et al., 2006; Jung et al., 1999; Rossi et al., 2001; Sekhon et al., 2004; Shin et al., 2007; Yanai et al., 2008). Hepatocyte Growth Factor (HGF) signaling through its tyrosine kinase receptor c-Met (Defrances et al., 1992; Iida et al., 2003; Ishikawa et al., 2001) is also required for hepatoblast proliferation (Birchmeier et al., 2003; Bladt et al., 1995; Moumen et al., 2007; Sachs et al., 2000; Schmidt et al., 1995). In addition to being a hepatocyte mitogen HGF also promotes hepatoblast migration (Block et al., 1996; Medico et al., 2001; Michalopoulos et al., 1993), in part by activating the small GTPase Arf6 (Suzuki et al., 2006).
Although Wnt/β-catenin signaling appears to repress liver fate during earlier endoderm patterning stages of development (section 3.1), by e10 in the liver bud β-catenin has the opposite effect and promotes hepatic growth (McLin et al., 2007; Micsenyi et al., 2004; Monga et al., 2003; Suksaweang et al., 2004; Tan et al., 2008). While the Wnt ligands involved are unclear (Zeng et al., 2007), in the chick Wnt9a is expressed in hepatic fibroblasts, and antisense depletion of Wnt9a inhibits liver bud growth in culture (Matsumoto et al., 2008). Multiple TGFβ ligands are also expressed in the liver bud mesenchyme (Pelton et al., 1991). Embryos with compound heterozygous mutations in the TGFβ transcriptional mediators Smad2 and Smad3 have hypoplastic livers (Weinstein et al., 2001), as do embryos deficient for the Smad interacting protein, Elf5 (Tang et al., 2003) and the receptor TGFβRIII (Stenvers et al., 2003)
Liver bud growth also requires retinoic acid signaling (Wang et al., 2006), which is controlled in part by the zinc finger transcription factor WT1 expressed in the STM and stellate cells (Ijpenberg et al., 2007). The homeobox genes Hlx and Lhx2 as well as N-myc are also expressed in the STM, and null mutations in each of these results in reduced hepatoblast proliferation and increased apoptosis (Giroux and Charron, 1998; Hentsch et al., 1996; Porter et al., 1997; Wandzioch et al., 2004), suggesting that they regulate the production of paracrine signals from the mesenchyme. Exactly how these different transcription factors and signaling pathways coordinate hepatic growth remains to be determined, but extensive cross talk appears to exist (Apte et al., 2006; Rossi et al., 2001; Weinstein et al., 2001). For example, explant cultures suggest that HGF and TGFβ signaling act in parallel converging on β1-integrin regulation (Weinstein et al., 2001). Moreover, FGF and HGF signaling stimulate many of the same intracellular kinase cascades (e.g. MAPK, JNK, Pi3K), and both have been reported to stimulate the activity of β-catenin in the liver bud, suggesting crosstalk with the Wnt pathway (Berg et al., 2007; Monga et al., 2002; Sekhon et al., 2004).
Return to top.
Hepatoblast Proliferation and Survival
A number of genes encoding regulators of proliferation, cell survival or metabolic stress are also required for liver bud growth including; c-jun (Eferl et al., 1999; Hilberg et al., 1993), Xbp1 (Reimold et al., 2000), Jumonji (Motoyama et al., 1997), Foxm1b (Krupczak-Hollis et al., 2004), MTF-1 (Gunes et al., 1998), Nrf1 (Chen et al., 2003), Tbx3 (Suzuki et al., 2008) and signal transduction components K-ras (Johnson et al., 1997), Pi3kr1 (Fruman et al., 2000), Raf1 (Mikula et al., 2001) and Sek1 (Ganiatsas et al., 1998; Nishina et al., 1999; Watanabe et al., 2002). Regulation of the inflammatory cytokine Tumor Necrosis Factor alpha (TNFα) is also important and embryos lacking components of the anti-apoptotic NFκβ complex exhibit TNFα mediated hepatoblast apoptosis (Beg et al., 1995; Bonnard et al., 2000; Doi et al., 1999; Li et al., 1999; Rosenfeld et al., 2000).
Return to top.
