The role of retinoids and retinoic acid receptors in normal hematopoiesis

The family of retinoic acid receptors (RARs: RARα, -β, and -γ) has remarkable pleiotropy characteristics, since the retinoic acid/RARs pathway is involved in numerous biological processes not only during embryonic development, but also in the postnatal phase and during adulthood. In this review, we trace the roles of RA/RARs signaling in the immune system (where this pathway has both an immunosuppressive role or is involved in the inflammatory response), in hematopoiesis (enhancing hematopoietic stem cell self-renewal, progenitor cells differentiation or maintaining the bone marrow microenvironment homeostasis), and in bone remodeling (where this pathway seems to have controversial effects on bone formation or osteoclast activation). Moreover, in this review is shown the involvement of RAR genes in multiple chromosomal rearrangements generating different fusion genes in hematological neoplasms, with a particular focus on acute promyelocytic leukemia and its variant subtypes. The effect of different RARs fusion proteins on leukemic transformation, on patients’ outcome, and on therapy response is also discussed.

Download Full-text

Role of GHF-1 in the Regulation of the Rat Growth Hormone Gene Promoter by Thyroid Hormone and Retinoic Acid Receptors

Journal of Biological Chemistry ◽

10.1074/jbc.273.42.27541 ◽

1998 ◽

Vol 273 (42) ◽

pp. 27541-27547 ◽

Cited By ~ 25

Author(s):

Teresa Palomino ◽

Domingo Barettino ◽

Ana Aranda

Keyword(s):

Growth Hormone ◽

Retinoic Acid ◽

Thyroid Hormone ◽

Gene Promoter ◽

Retinoic Acid Receptors ◽

Growth Hormone Gene ◽

Rat Growth

Download Full-text

The role of retinoic acid receptors in activated hepatic stellate cells

Medical Hypotheses ◽

10.1016/j.mehy.2013.04.045 ◽

2013 ◽

Vol 81 (2) ◽

pp. 222-224 ◽

Cited By ~ 5

Author(s):

Yoshihiro Mezaki ◽

Mayako Morii ◽

Taku Hebiguchi ◽

Kiwamu Yoshikawa ◽

Noriko Yamaguchi ◽

...

Keyword(s):

Retinoic Acid ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Retinoic Acid Receptors ◽

Activated Hepatic Stellate Cells

Download Full-text

Defective lens fiber differentiation and pancreatic tumorigenesis caused by ectopic expression of the cellular retinoic acid-binding protein I

Development ◽

10.1242/dev.119.2.363 ◽

1993 ◽

Vol 119 (2) ◽

pp. 363-375

Author(s):

A.V. Perez-Castro ◽

V.T. Tran ◽

M.C. Nguyen-Huu

Keyword(s):

Retinoic Acid ◽

Binding Proteins ◽

Binding Protein ◽

Ectopic Expression ◽

Retinoic Acid Receptors ◽

Acid Binding Protein ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Retinoic Acid Binding Proteins

All-trans retinoic acid, a metabolite of retinol, is a possible morphogen in vertebrate development. Two classes of cellular proteins, which specifically bind all-trans retinoic acid, are thought to mediate its action: the nuclear retinoic acid receptors (RAR alpha, beta, gamma), and the cytoplasmic binding proteins known as cellular retinoic acid-binding proteins I and II (CRABP I and II). The function of the retinoic acid receptors is to regulate gene transcription by binding to DNA in conjunction with the nuclear retinoid X receptors (RXR alpha, beta, gamma), which in turn have 9-cis retinoic acid as a ligand. Several lines of evidence suggest that the role of the cellular retinoic acid-binding proteins is to control the concentration of free retinoic acid reaching the nucleus in a given cell. Here, we have addressed the role of the cellular retinoic acid-binding protein I in development by ectopically expressing it in the mouse lens, under the control of the alpha A-crystallin promoter. We show that this ectopic expression interferes with the development of the lens and with the differentiation of the secondary lens fiber cells, causing cataract formation. These results suggest that correct regulation of intracellular retinoic acid concentration is required for normal eye development. In addition, the generated transgenic mice also present expression of the transgene in the pancreas and develop pancreatic carcinomas, suggesting that overexpression of the cellular retinoic acid-binding protein is the cause of the tumors. These results taken together provide evidence for a role of the cellular retinoic acid-binding protein in development and cell differentiation. The relevance of these findings to the possible role of the cellular retinoic acid-binding proteins in the transduction of the retinoic acid signal is discussed.

Download Full-text

The role of retinoic acid receptors in neurite outgrowth from different populations of embryonic mouse dorsal root ganglia

Journal of Cell Science ◽

10.1242/jcs.113.14.2567 ◽

2000 ◽

Vol 113 (14) ◽

pp. 2567-2574

Author(s):

J. Corcoran ◽

B. Shroot ◽

J. Pizzey ◽

M. Maden

Keyword(s):

Retinoic Acid ◽

Neurite Outgrowth ◽

Dorsal Root ◽

Retinoic Acid Receptors ◽

Embryonic Mouse ◽

Different Populations ◽

Alpha Beta ◽

Beta 2 ◽

X Receptors

Dorsal root ganglion (DRG) neurons can be categorised into at least three types, based upon their neurotrophin requirement for survival. We have analysed the expression of the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) in NGF, NT-3 and BDNF dependent neurons isolated from embryonic day (E)13.5 mouse DRG. We show that each population of neurons expressed each of the three RXRs, (alpha), (beta) and (gamma); however, whilst the NGF and NT-3 dependent neurons expressed each of the RARs (alpha), (beta) and (gamma), the BDNF dependent neurons only expressed RAR(alpha) and (beta). When retinoic acid was added to each of the neuronal classes only the NGF and NT-3 dependent neurons responded by extending neurites, and this response involved the upregulation of RAR(beta)(2). This specificity was confirmed by the use of receptor-selective agonists as only a RAR(beta)-selective compound stimulated neurite outgrowth. These results suggest a role for RA acting via RAR(beta)(2) in the outgrowth of neurites.

Download Full-text

Hindbrain patterning involves graded responses to retinoic acid signalling

Development ◽

10.1242/dev.128.12.2199 ◽

2001 ◽

Vol 128 (12) ◽

pp. 2199-2208 ◽

Cited By ~ 7

Author(s):

Valérie Dupé ◽

Andrew Lumsden

Keyword(s):

Retinoic Acid ◽

Neural Tube ◽

Retinoic Acid Receptors ◽

Chick Embryos ◽

Anteroposterior Axis ◽

Retinoic Acid Signalling ◽

Graded Responses ◽

Acid Deficiency ◽

Precise Role

Several recent studies have shown that retinoic acid signalling is required for correct patterning of the hindbrain. However, the data from these studies are disparate and the precise role of retinoic acid signalling in patterning the anteroposterior axis of the neural tube remains uncertain. To help clarify this issue, we have cultured a staged series of chick embryos in the presence of an antagonist to the all three retinoic acid receptors. Our data indicate that retinoic acid is the transforming signal involved in the expansion of posterior hindbrain structures. We find that the hindbrain region of the neural tube down to the level of the sixth somite acquires the identity of rhombomere 4 when retinoic acid signalling is blocked. Specification of future rhombomere boundaries has a retinoic acid dependency between stage 5 and stage 10+ that is lost progressively in an anterior-to-posterior sequence. Furthermore, the application of various concentrations of antagonist shows that successively more posterior rhombomere boundaries require progressively higher concentration of endogenous retinoic acid for their correct positioning, a result that strengthens the hypothesis that a complex retinoid gradient acts to pattern the posterior hindbrain. Our dissection of early retinoic acid functions allows us to re-interpret the wide disparity of hindbrain phenotypes previously observed in various models of retinoic acid deficiency.

Download Full-text