Retinoid signalling

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

Wang, X.D. et al., Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke, J. Natl. Cancer Inst., 91, 60, 1999. 

Impairment of the retinoid signal transduction pathways occurs as a result of prolonged UV exposure. Down regulation of nuclear receptors for Vitamin A occurs,269 resulting in a functional deficiency of Vitamin A. Application of Vitamin A derivatives would appear to be an obvious treatment modality. Topical application of Vitamin A does increase the HA in the epidermal layer, increasing the thickness of the HA meshwork after prolonged treatment.270 Vitamin A thus enhances repair, as can be demonstrated in photo-aged hairless mouse model.271 The decline in GAG, and in particular HA deposition that occurs with UVB irradiation, can be entirely prevented by retinoic acid treatment. 

Chambon P The retinoid signaling pathway molecular and genetic analysis. Cell Biol. 5 115-125,1994. 

Mark M, Ghyselinck NB, Wendling O, Dupe V, Mascrez B, Kastner P, and Chambon P (1999) A genetic dissection of the retinoid signalling pathway in the mouse. Proceedings of the Nutrition Society 58, 609-13. 

P. Kastner, M. Mark, N. Ghyselinck, W. Krezel, V. Dupe, J. M. Grondona, and P. Chambon. Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development, 124 (2), 313-326, 1997. 

Giguere, V. Retinoic acid receptors and cellular retinoid binding proteins complex interplay in retinoid signaling. Endocr. Rev. 15 61—79, 1994. 

Nilsson, C.B. and H. Hakansson. The retinoid signaling system - a target in dioxin toxicity. Crit. Rev. Toxicol. 32 211-232, 2002. 

Retinoid signaling is essential for numerous ontogenic programs (Lohnes et al., 1995 Eichele, 1997 Niederreither et al., 1999 Maden, 2000), a general discussion of which is beyond the scope of this review. Of particular relevance, however, is the role for RA in regulation of Hox gene expression. A key observation... 

Gavalas, A., Krumlauf, R. 2000. Retinoid signalling and hindbrain patterning. Curr. Opin. Genet. Dev. 10, 380-386. 

Kolm, P.J., Apekin, V., Sive, H. 1997. Xenopus hindbrain patterning requires retinoid signaling. Dev. Biol. 192, 1-16. 

The retinoid signal is transduced primarily by two distinct ligand-activated transcription factors the retinoic acid receptors (RARs) and retinoid receptors (RXRs) (Chambon, 1996). There are three distinct genes in each of the RAR and RXR gene families (a, j3, and y), all of which are activated by RA. However, not all the members of each gene family are expressed in the hindbrain. RARa is expressed up to the r3/4 border while RAR/3 is expressed uniformly in the neural tube with an anterior limit at the r6/7 boundary (Fig. 5) (Ruberte et al., 1990 Mendelsohn et al., 1991 Ruberte et al., 1991a,b, 1992, 1993 Dolle et al., 1994 Mendelsohn et al., 1994). 

Thus, RAREs convey the universal ability to drive early abundant expression of Hox genes within the neurectoderm. Moreover, they set the rostral limits of Hox gene expression and are thus able to interpret positional information supplied by posteriorizing signals from either the mesoderm or neural plate. Retinoid signaling therefore helps establish Hox gene co-linearity by directly activating the 3 members of the complex within defined spatial-temporal domains. 

Lumsden, 2001 Wendling et al., 2001). Blocking retinoid signaling therefore results in a caudal truncation of the hindbrain, with hindbrain disruptions being progressively more severe the earlier the treatment. In the most extreme form of retinoid deprivation elicited by antagonist treatments, the caudal hindbrain becomes truncated below r4, while the remaining rhombomeres are expanded. 

As the absence of retinoid signaling leads to an anteriorization of the hindbrain, increases in retinoid signaling should therefore lead to a posteriorization of the hindbrain. Predictably, inactivation of Cyp26Al in the mouse, a RA-catabolizing enzyme expressed in r2, leads to a mild posterior transformation of the anterior hindbrain. Concomitant with a rostral expansion of Hoxbl are enhanced levels of Hoxbl expression in r4 (Abu-Abed et al., 2001 Sakai et al., 2001). 

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