Role Of Specific Raregulated Genes

The availability of this large battery of RA-regulated genes associated with differentiation of EC and ES cells allows more hypothesis-driven experiments. These studies are focused on the determination of the specific role of individual genes during the differentiation process. The long-term goal of these studies is to understand the sequence of events at the molecular level during RA-induced differentiation in EC and ES cells. Many of these genes are expressed in early embryos and are likely to be important players in embryogenesis (Tables I and II).

RARb2 and RARa2: The expression of two RARs, RAR^2 and RARa2, is rapidly increased following RA treatment of F9 cells and P19 cells (Hu and Gudas, 1990; Qin et al., 2004a; Shen et al., 1991). This increase in RARb2 and RARa2 expression is mediated by RAREs located in the promoter of each of these genes (Shen et al., 1991).

The role of RAR^2 in mediating RA-dependent differentiation of F9 cells has been studied utilizing RARb2 ^ F9 cells (Faria et al., 1999). RARb2 ^ F9 cells have an altered morphology and fail to fully differentiate upon RA treatment. These cells fail to growth arrest after RA treatment suggesting that RARb2 plays an important role in mediating growth. RAR^2 has been shown to be necessary for the RA-dependent increase in the protein level of p27 (an important cell cycle regulatory gene) by elevating p27 mRNA levels, rate of translation, and half-life of p27 (Li et al., 2004). Moreover, RARb2 is required for the sustained expression of a number of other RA-responsive genes. A comparison of the gene expression profiles in wild-type and RARb2 F9 cells demonstrates that RAR^2 regulates the expression of a wide variety of genes including transcription factors, cell surface-signaling

TABLE I. Mechanism of Action for Selected Genes During Endodermal Differentiation

Gene Cell line RA response Mechanistic studies

Gene Cell line RA response Mechanistic studies

TABLE I. Mechanism of Action for Selected Genes During Endodermal Differentiation

RARg

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