The Role of Gas1 in Embryonic Development and its Implications for Human Disease

Abstract

Growth arrest specific gene 1 (Gas1) has long been regarded as a cell cycle inhibitor of the G 0 to S phase transition. How GAS1, a GPI-anchored plasma membrane protein, directs intracellular changes without an extracellular ligand or a transmembrane protein partner has been puzzling. A recent series of biochemical and molecular genetic studies assigned the mammalian Hedgehog (HH) growth factor to be a ligand for GAS1 in vitro and in vivo. HH has enjoyed considerable attention for its profound role in embryonic patterning as a classic morphogen, i.e. inducing various cell types in a concentrationdependent manner. GAS1 appears to help transform the HH concentration gradient into its morphogenic activity gradient by acting cooperatively with the HH receptor, the 12-transmembrane protein Patched 1 (PTC1). These findings provoke intriguing thoughts on how HH and GAS1 may coordinate cell proliferation and differentiation to create biological patterns. The role of HH extends to human genetic diseases, stem cell renewal, and cancer growth, and we consider the possibility of GAS1's involvement in these processes as well.Precise integration between cell proliferation and cell type specification during embryogenesis directs the formation and function of each tissue. Integration between these two programs in a given cell is largely determined by intercellular signaling molecules. Here, we review the recent 'unlikely marriage' between two extracellular molecules, GAS1 and HH, and the implications on coordinated cell proliferation and cell type specification. Gas1 the cell cycle InhIbItorIn 1988, Gas1 was identified as one of six genes that were transcriptionally up-regulated in NIH3T3 cells arrested in cell cycle upon serum starvation, a presumed G 0 arrest. 1 Among the six initially identified growth arrest specific (hence Gas) genes, only Gas1 could suppress cell cycle progression when overexpressed in non-transformed and certain oncogene-transformed NIH3T3 cells. [2][3][4] Because GAS1 overexpressing cells did not incorporate BrdU, it was thought that GAS1 blocked the G 0 to S phase transition. Deletion analysis of GAS1, an outer plasma membrane glycosylphosphatidylinositol (GPI)-linked protein of 37 kDa, concluded that it could induce growth arrest without its GPI anchor, suggesting that it acts through another membrane partner. 5,6 Interestingly, GAS1-induced growth arrest depended on the tumor suppressor gene p53. 7,8 Furthermore, c-Myc and v-Src, powerful proliferation promoting factors, repressed Gas1 expression, suggesting that Gas1 downregulation is an associated step in the promotion of proliferation. 9,10 By contrast, senescent fibroblast cells, though cease proliferating, do not express Gas1. 11 These studies together suggest that GAS1 is a negative cell growth regulator rather than a senescence mediator. However, evidence to demonstrate such a function for Gas1 in an animal model is lacking.

Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network

“…An analysis of Cdo, Boc and Gas1 mouse mutants confirms the importance of Cdo and Gas1 in the patterning of the ventral neural tube and points to the existence of functional compensation amongst these proteins (Allen et al, 2007;Martinelli and Fan, 2007;Tenzen et al, 2006). The onset of Cdo expression at the ventral midline of the neural tube occurs at the same time as floor plate specification (Fig.…”

“…These include the related transmembrane proteins Cdo (also known as Cdon) and Boc, and the glycosylphosphatidylinositol (GPI)-linked protein Gas1 (Fig. 4) (Allen et al, 2007;Martinelli and Fan, 2007;Tenzen et al, 2006;Yao et al, 2006;Zhang et al, 2006). Surprisingly, their expression is generally, but not always, inhibited by Shh signaling.…”

“…This suggests that Cdo might act to boost the response to Shh signaling and that this increased signal is necessary for normal floor plate induction. The deletion of Gas1 also results in a loss of cell identities in the ventral neural tube, a defect that is enhanced in Shh +/-embryos (Allen et al, 2007;Martinelli and Fan, 2007). Furthermore, when Gas1 and Cdo gene dosage is progressively lowered, the neural phenotype becomes progressively Shh is produced as a large precursor protein that undergoes a series of post-translational modifications prior to secretion.…”

A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene

“…By contrast, one gene, Gas1, was markedly down-regulated (∼11-fold) in B16-F10 cells. Gas1 encodes a pleiotropic 45-kDa glycosylphosphatidylinositol-anchored membrane protein (Stebel et al 2000) that has been shown to play a role in both negative (Del Sal et al 1992;Lee et al 2001;Mellstrom et al 2002;Zamorano et al 2003Zamorano et al , 2004 and positive regulation of cell growth (Liu et al 2001;Spagnuolo et al 2004), as well as in embryonic development through regulation of Sonic Hedgehog signaling (for review, see Martinelli and Fan 2007b).…”

A Sonic Hedgehog Missense Mutation Associated with Holoprosencephaly Causes Defective Binding to GAS1

“…We have previously reported that microform HPE develops in growth arrest-specific gene 1 (Gas1) mutant mice (3,4). Additionally, we determined that the 37-kDa, cell surface-presented, and glycosylphosphatidylinositol-anchored GAS1 protein binds to the secreted cell-cell signaling protein Sonic hedgehog (SHH) and that it functions as a cell-autonomous enhancer of SHH signaling activity (3,5,6).…”