Catherine S. Lee

The initiation of liver development is dependent on Foxa transcription factors

The specification of the vertebrate liver is thought to occur in a two-step process, beginning with the establishment of competence within the foregut endoderm for responding to organ-specific signals, followed by the induction of liver-specific genes. On the basis of expression and in vitro studies, it has been proposed that the Foxa transcription factors establish competence by opening compacted chromatin structures within liver-specific target genes. Here we show that Foxa1 and Foxa2 (forkhead box proteins A1 and A2) are required in concert for hepatic specification in mouse. In embryos deficient for both genes in the foregut endoderm, no liver bud is evident and expression of the hepatoblast marker alpha-fetoprotein (Afp) is lost. Furthermore, Foxa1/Foxa2-deficient endoderm cultured in the presence of exogenous fibroblast growth factor 2 (FGF2) fails to initiate expression of the liver markers albumin and transthyretin. Thus, Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis.

Evidence that the WNT-inducible growth arrest-specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite

The dorsal–ventral polarity of the somite is controlled by antagonistic signals from the dorsal neural tube/surface ectoderm, mediated by WNTs, and from the ventral notochord, mediated by sonic hedgehog (SHH). Each factor can act over a distance greater than a somite diameter in vitro, suggesting they must limit each others actions within their own patterning domains in vivo. We show here that the growth-arrest specific gene 1 (Gas1), which is expressed in the dorsal somite, is induced by WNTs and encodes a protein that can bind to SHH. Furthermore, ectopic expression of Gas1 in presomitic cells attenuates the response of these cells to SHH in vitro. Taken together, these data suggest that GAS1 functions to reduce the availability of active SHH within the dorsal somite.

Embryonic expression patterns of the mouse and chick Gas1 genes.

Control of cell proliferation is essential to generate the defined form of a multi-cellular organism. While much is known about the regulators for cell cycle progression, relatively little is known about the state of growth arrest. Growth arrest (G0) is defined as a cell in a metabolically active but proliferation-quiescent state (reviewed in Baserga (1985) The Biology of Cell Reproduction), typically induced by serum starvation in vitro. Using subtractive hybridization, Schneider et al. (Cell 54 (1988) 787) identified six genes (Gas1 through Gas6) whose expressions are upregulated in serum-deprived NIH3T3 cells. Among the Gas genes, Gas1 is the only one that can cause growth arrest when expressed in cultured cell (Cell 70 (1995) 595; Int. J. Cancer 9 (1998) 569). Here, we describe for the first time the expression pattern of Gas1 during mouse embryogenesis. Our data reveal that Gas1 is expressed in many regions that the cells are actively proliferating and suggest that it may have other roles during development than negatively regulating cell proliferation. Furthermore, we have cloned the chick GAS1 gene and documented the similarity and divergence of Gas1 gene expression patterns between the two species.