Inductive signalling between mesenchyme and epithelium is a common feature in organogenesis, and hepatogenesis is no exception. It has been known for some time that fibroblast growth factor (FGF) signals produced by the cardiac mesoderm (CM) induce liver formation in the anterior gut. Now Rossi and colleagues show that liver specification also requires a bone morphogenetic protein (BMP) signal that comes from septum transversum (ST) mesenchyme, which contributes to the epicardium and the diaphragm. With the FGF signals from the CM, this signal specifies which part of the anterior gut endoderm becomes the liver.

Classical transplantation studies established that the CM was necessary and sufficient for early hepatogenesis. Equipped with a new, ST-specific marker, Rossi et al. realized that ST cells are frequently present in CM explants because of the tight association between these tissues. This raised the possibility that they too could function in early hepatogenesis.

To investigate further, the authors analysed the ST mesenchyme in a Bmp4 LacZ mouse in which LacZ disrupts the Bmp4. Expression of LacZ was strong in the ST and early hepatogenesis was severely retarded in Bmp4LacZ homozygous mice. A more severe liver phenotype only became apparent when exogenous noggin — a general BMP antagonist — was added, indicating that other members of the BMP family, also expressed in the ST, are required for hepatogenesis and might compensate for the loss of Bmp4 in the Bmp4LacZ mice. They also noticed that the expression of albumin — an early liver-specific gene — was absent when the BMPs were blocked by noggin and that the FGF signal from the CM could not substitute for the BMP-induced albumin expression.

Rossi et al. also concluded that, by inducing liver development, the BMP signal from the ST and the FGF signal from the CM indirectly prevent pancreatic development. This is because in the presence of the BMP signal, which leads to albumin induction, expression of Pdx1 — an early pancreatic marker — is lost. Conversely, in the absence of the BMP signal, albumin is not induced, but Pdx1 is expressed. Furthermore, the authors showed that the BMP signal is, at least in part, mediated by the Gata4 transcription factor.

The molecules behind the mesodermal induction signals required for the development of the different organs that arise from the gut endoderm gradually begin to reveal their identities. Thanks to Rossi and colleagues, hepatogenesis can now be added to the list of other developmental processes that involve the combined action of BMP and FGF signals.