Retinoic acid (RA), the most potent natural form of vitamin A, plays an important role in mediating the growth and differentiation of both normal and transformed cells (Chambon, 1996; Soprano and Soprano, 2003). It is essential for many diverse biological functions including growth, vision, reproduction, embryonic development, diVerentiation of epithelial tissues, and immune responses.

The role of vitamin A during embryonic development was first recognized in the 1930s when maternal vitamin A deficiency was found to be associated with a number of defects (Hale, 1937; Mason, 1935). This was eventually termed the vitamin A-deficiency syndrome. Later, it was demonstrated that an excess of vitamin A caused a number of congenital abnormalities (Cohlan, 1953). Clearly the maintenance of retinoid homeostasis is critical during embryonic development. Following these initial observations, a large number of studies have examined the role of vitamin A and more specifically RA, retinoic acid receptors (RARs), and retinoid X receptors (RXRs) during embryonic development. This work has been extensively reviewed by a number of investigators (for reviews see Clagett-Dame and De Luca, 2002; Mark et al., 2006; Ross et al., 2000; Soprano and Soprano, 1995; Zile, 2001).

RA is also an important regulatory molecule for controlling cell growth and differentiation in both the adult and the embryo. It is critical for the maintenance of the diVerentiated state of all epithelial cells in the body and for hematopoietic cell differentiation (for reviews see De Luca et al., 1995;

Oren et al., 2003). In vitro, RA induces differentiation of pluripotent embryonal carcinoma (EC) and embryonic stem (ES) cell lines into a number of specific cell types. ES cells are transiently present in the embryo and small numbers are also believed to be present in adult tissues. RA is a critical regulator of embryonic neurogenesis and has been shown to play an important role during adult neurogenesis in vivo (Jacobs et al., 2006; McCaffery and Drager, 2000). Therefore, the study of RA-induced differentiation in vitro is important to understand early embryonic development and differentiation of adult stem cells in vivo.

This chapter will summarize the current state of knowledge pertaining to the role of RA in the differentiation of EC and ES cells. Since the effects of RA during differentiation are due to the regulation of gene expression, we will begin by reviewing briefly the remarkable progress that has been made in understanding the mode of action of retinoids at the molecular level. We will then describe several model systems used to study RA-induced differentiation in vitro. Finally, we will review the current information pertaining to the role of retinoid nuclear receptors and RA-regulated genes during differentiation of EC and ES cells to a number of differentiated cell types.

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