Role of Retinoic Acid in the Differentiation of Embryonal Carcinoma and Embryonic Stem Cells

doi:10.1016/S0083-6729(06)75003-8

Vitamins & Hormones

Volume 75, 2007, Pages 69-95

https://doi.org/10.1016/S0083-6729(06)75003-8 Get rights and content

Retinoic acid (RA), the most potent natural form of vitamin A, plays an important role in many diverse biological processes such as embryogenesis and cellular differentiation. This chapter is a review of the mechanism of action of RA and the role of specific RA‐regulated genes during the cellular differentiation of embryonal carcinoma (EC) and embryonic stem (ES) cells. RA acts by binding to its nuclear receptors and inducing transcription of specific target genes. The most studied mouse EC cell lines include F9 cells, which can be induced by RA to differentiate into primitive, parietal, and visceral endodermal cells; and P19 cells, which can differentiate to endodermal and neuronal cells upon RA treatment. ES cells can be induced to differentiate into a number of different cell types; many of which require RA treatment. Over the years, many RA‐regulated genes have been discovered in EC and ES cells using a diverse set of techniques. Current research focuses on the elucidation how these genes affect differentiation in EC and ES cells using a variety of molecular biology approaches. However, the exact molecule events that lead from a pluripotent stem cell to a fully differentiated cell following RA treatment are yet to be determined.

Introduction

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 2003). It is essential for many diverse biological functions including growth, vision, reproduction, embryonic development, differentiation 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 2002, Mark 2006, Ross 2000, 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 differentiated state of all epithelial cells in the body and for hematopoietic cell differentiation (for reviews see De Luca 1995, Oren 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 2006, McCaffery 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.

Section snippets

Molecular Mechanism of Action of RA

RA functions by binding to ligand‐inducible transcription factors (nuclear receptor proteins belonging to the steroid/thyroid hormone receptor superfamily) that activate or repress the transcription of downstream target genes (for review see Chambon 1996, Soprano 2003). Six nuclear receptors (termed RARα, RARβ, RARγ, RXRα, RXRβ, and RXRγ), encoded by distinct genes, have been demonstrated to mediate the actions of RA. The natural metabolites all‐trans RA (atRA) and 9‐cis RA are high‐affinity

Model Systems to Study Differentiation

In order to study the role of RA during cellular differentiation in vitro, it is necessary to have available model systems that closely resemble development in vivo.

Mouse EC and ES cell lines have been well characterized and there are also several human lines available. These pluripotent cell lines can be maintained as undifferentiated cells and can be induced to differentiate in vitro to virtually any cell type. Furthermore, they are very amenable to genetic manipulations making them excellent

Role of RARs

There is an overwhelming amount of evidence that functional RARs and RXRs are obligatory in mediating RA‐dependent differentiation of EC and ES cells. Studies with an RA‐nonresponsive mutant line of P19 cells (termed RAC65) have demonstrated the importance of functional RARs in RA‐dependent differentiation of P19 cells. RAC65 cells do not differentiate after treatment with RA (Jones‐Villeneuve et al., 1983). These cells carry a rearrangement of one of the RARα genes resulting in the production

RA‐Regulated Genes

There has been great effort over the last 25 years by many investigators to elucidate the cascade of gene expression events that ultimately results in the differentiated phenotype displayed by EC and ES cells following RA treatment. The first step to achieve this goal has been to identify genes whose expression is altered by RA during differentiation along a number of different pathways. The approaches used to address this question have changed over the years taking advantage of the major

Role of Specific RA‐Regulated 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

Conclusions

In vitro differentiation of EC and ES cells by RA mimics events that occur during early development. Differentiation by RA requires functional RARs and RXRs. The expression of a large battery of genes is modulated upon RA treatment of EC and ES along several differentiation pathways. Current studies are addressing the role of these genes in mediating RA‐dependent differentiation. However, the exact molecule events that lead from a pluripotent cell to a fully differentiated cell following RA

Acknowledgments

The support of National Institutes of Health grant DK070650 is gratefully acknowledged.

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Role of Retinoic Acid in the Differentiation of Embryonal Carcinoma and Embryonic Stem Cells

Introduction

Section snippets

Molecular Mechanism of Action of RA

Model Systems to Study Differentiation

Role of RARs

RA‐Regulated Genes

Role of Specific RA‐Regulated Genes

Conclusions

Acknowledgments

Dev. Biol.

Mol. Cells

J. Biol. Chem.

FEBS Lett.

Mol. Cell. Endocrinol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Trends Neurosci.

FEBS Lett.

FEBS Lett.

Mech. Dev.

Cell

Bone

Mech. Dev.

Mech. Dev.

Differentiation

J. Biol. Chem.

Exp. Cell Res.

Cell

J. Biol. Chem.

Dev. Biol.

Cytokine Growth Factor Rev.

Cell

Exp. Cell Res.

Cell

Brain Res. Mol. Brain Res.

Curr. Opin. Genet. Dev.

Differentiation

J. Biol. Chem.

J. Biol. Chem.

Cell

Biochem. Biophys. Res. Commun.

Differential display of proteins involved in the neural differentiation of mouse embryonic carcinoma P19 cells by comparative proteomic analysis

Proteomics

Cyclophilin A peptidyl‐prolyl isomerase activity promotes ZPR1 nuclear export

Mol. Cell. Biol.

From embryonal carcinoma cells to neurons: The P19 pathway

BioEssays

ES cell neural differentiation reveals a substantial number of novel ESTs

Funct. Integr. Genomics

Rex‐1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct‐3/4 and Oct‐6 binding to an octamer site and a novel protein, Rox‐1, binding to an adjacent site

Mol. Cell. Biol.

Purified N‐cadherin is a potent substrate for the rapid induction of neurite outgrowth

J. Cell Biol.

Loss of retinoic acid receptor γ function in F9 cells by gene disruption results in aberrant Hoxa‐I expression and differentiation upon retinoic acid treatment

Proc. Natl. Acad. Sci. USA

Targeted disruption of retinoic acid receptor α (RARα) and RARγ results in receptor‐specific alterations in retinoic acid‐mediated differentiation and retinoic acid metabolism

Mol. Cell. Biol.

A decade of molecular biology of retinoic acid receptors

FASEB J.

Distinct retinoid X receptors‐retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells

Mol. Cell. Biol.

Specific and redundant function of retinoid X receptor/retinoic acid receptor heterodimers in differentiation, proliferation, and apoptosis of F9 embryonal carcinoma cells

J. Cell Biol.

Effects of altered expression and localization of cyclophilin A on differentiation of p19 embryonic carcinoma cells

Cell. Mol. Neurobiol.

RXRα−null F9 embryonal carcinoma cells are resistant to the differentiation, anti‐proliferative and apoptotic effects of retinoids

EMBO J.

The role of vitamin A in mammalian reproduction and embryonic development

Annu. Rev. Nutr.

Excessive intakes of vitamin A as a cause of congential anomalies in the rat

Science

The Sry‐related HMG box‐containing gene Sox6 is expressed in the adult testis and developing nervous system of the mouse

Nucleic Acids Res.

Differentiation of embryonic stem cells into adipocytes in vitro

J. Cell Sci.

Retinoids in differentiation and neoplasia

Sci. Med.