3 Retinoic Acid-Regulated Target Genes During Development …
59
during RA-induced cell differentiation. During the two last decades, the publication
of the genome sequences of various organisms has facilitated advances in massive
parallel sequencing and in bioinformatics analysis of genome-wide data sets. These
novel technologies, named New Generation sequencing (NGS), have revolutionized
the field and have provided a global integrated picture of RA-regulated gene networks
and the regulatory programs that are involved in cell fate decisions during embryonal
carcinoma and embryonic stem cells differentiation
History
In the middle of the twentieth century, it was observed that maternal vitamin A deficiency (VAD) induces multiple malformations in embryos (Warkany and Schraffenberger 1946; Fig. 3.1). In the early 1980s, it was found that exogenously administered
RA modifies the regenerate pattern of amphibian limbs (Maden 1982; Stocum 1991)
and induces striking changes in chick limb development that result in the formation
of additional sets of digits (Tickle et al. 1982). Thaller and Eichele suggested that an
RA gradient might establish the normal anterior–posterior pattern of chicken limb
development (Thaller and Eichele 1987; Fig. 3.1).
Another important observation was that ECCs, which markedly resemble the
pluripotential embryonic cells from the blastocysts, have the ability to differentiate
in response to RA. F9, the prototypic murine ECC line, differentiates into primitive,
parietal or visceral endodermal cells in response to RA, depending on the culture
conditions (Hogan et al. 1981; Strickland and Mahdavi 1978; Strickland et al. 1980).
Other ECC lines, such as the murine P19 cell line and the human NT2/D1 cell line
differentiate into neuronal cells after RA addition (Jones-Villeneuve et al. 1982).
Interestingly, ESCs, when treated with RA, were also found to become progenitors
that differentiate into glutamatergic neurons (Bibel et al. 2004). Thus, ECCs and
ESCs have been considered important models for analyzing RA-regulated genes
during early development.
In the early 1990s, there was tremendous interest in whether the activities of RA
reflected a genetic mechanism. Initially, a limited number of RA responsive genes
were identified in ECCs using various cDNA screening methods with differential or
subtractive hybridization (Fig. 3.1; Table 3.1). These genes were essentially involved
in the expression of Bone Morphogenic Proteins (BMPs) (Rogers et al. 1992), basement membrane and extracellular matrix components (laminin I and collagen IV)
(Vasios et al. 1989, 1991; Wang and Gudas 1988), homeobox containing proteins
(Hoxb2 (Jonk et al. 1994) and Hox1.6/Hoxa1 (LaRosa and Gudas 1988), enzymes
involved in glucose metabolism (Fructose biphosphatase 2) (Nomura et al. 1994),
the retinoic acid receptor RARβ2 (Hu and Gudas 1990; Zelent et al. 1989), and the
cellular RA binding protein CRABPII (Giguere et al. 1990). Complementary in situ
hybridization experiments performed with sections of mouse embryos confirmed that
the expression patterns found during the in vitro differentiation of ECCs reflected
what happens during embryonic development (Dolle et al. 1989, 1990; Ruberte et al.
59
during RA-induced cell differentiation. During the two last decades, the publication
of the genome sequences of various organisms has facilitated advances in massive
parallel sequencing and in bioinformatics analysis of genome-wide data sets. These
novel technologies, named New Generation sequencing (NGS), have revolutionized
the field and have provided a global integrated picture of RA-regulated gene networks
and the regulatory programs that are involved in cell fate decisions during embryonal
carcinoma and embryonic stem cells differentiation
History
In the middle of the twentieth century, it was observed that maternal vitamin A deficiency (VAD) induces multiple malformations in embryos (Warkany and Schraffenberger 1946; Fig. 3.1). In the early 1980s, it was found that exogenously administered
RA modifies the regenerate pattern of amphibian limbs (Maden 1982; Stocum 1991)
and induces striking changes in chick limb development that result in the formation
of additional sets of digits (Tickle et al. 1982). Thaller and Eichele suggested that an
RA gradient might establish the normal anterior–posterior pattern of chicken limb
development (Thaller and Eichele 1987; Fig. 3.1).
Another important observation was that ECCs, which markedly resemble the
pluripotential embryonic cells from the blastocysts, have the ability to differentiate
in response to RA. F9, the prototypic murine ECC line, differentiates into primitive,
parietal or visceral endodermal cells in response to RA, depending on the culture
conditions (Hogan et al. 1981; Strickland and Mahdavi 1978; Strickland et al. 1980).
Other ECC lines, such as the murine P19 cell line and the human NT2/D1 cell line
differentiate into neuronal cells after RA addition (Jones-Villeneuve et al. 1982).
Interestingly, ESCs, when treated with RA, were also found to become progenitors
that differentiate into glutamatergic neurons (Bibel et al. 2004). Thus, ECCs and
ESCs have been considered important models for analyzing RA-regulated genes
during early development.
In the early 1990s, there was tremendous interest in whether the activities of RA
reflected a genetic mechanism. Initially, a limited number of RA responsive genes
were identified in ECCs using various cDNA screening methods with differential or
subtractive hybridization (Fig. 3.1; Table 3.1). These genes were essentially involved
in the expression of Bone Morphogenic Proteins (BMPs) (Rogers et al. 1992), basement membrane and extracellular matrix components (laminin I and collagen IV)
(Vasios et al. 1989, 1991; Wang and Gudas 1988), homeobox containing proteins
(Hoxb2 (Jonk et al. 1994) and Hox1.6/Hoxa1 (LaRosa and Gudas 1988), enzymes
involved in glucose metabolism (Fructose biphosphatase 2) (Nomura et al. 1994),
the retinoic acid receptor RARβ2 (Hu and Gudas 1990; Zelent et al. 1989), and the
cellular RA binding protein CRABPII (Giguere et al. 1990). Complementary in situ
hybridization experiments performed with sections of mouse embryos confirmed that
the expression patterns found during the in vitro differentiation of ECCs reflected
what happens during embryonic development (Dolle et al. 1989, 1990; Ruberte et al.