RA and its isomer, 9-ds-retinoic acid (9cRA), serve as ligands that activate ligand-activated transcription factors that belong to a superfamily of nuclear receptors.10 This superfamily of related genes expresses nuclear receptors for steroids (the female sex hormones estrogen and progesterone, the mineralocorticoid aldoster-one, the glucocorticoid cortisol, the male sex hormones testosterone and dihy-drotestosterone), prostanoids, the thyroid hormone, the hormonal form of vitamin D, calcitriol, and peroxisome proliferators. Additionally, more than 50 orphan receptors belong to this family. Two classes of retinoid receptors occur: retinoic acid receptors (RAR) and retinoid X receptors (RXR). Each has three different versions (a, p, and y) encoded by distinct genes. Each version also has multiple isoforms resulting from differential promoter use and alternative RNA splicing. Thus, multiple forms of each occur (e.g., RARa1, RARa2, etc.). Moreover, RAR functions as a heterodimer with RXR. The multiple forms of both RAR
and RXR predict 48 different combinations. Several other receptors (e.g., vitamin D receptor; peroxisome proliferator activated receptors; thyroid hormone receptor) function as heterodimers with RXR. RXRs therefore seem to serve as "master" permissive factors for several hormones. Vertebrates conserve each receptor, e.g., greater sequence similarity occurs between mouse and human RARa than between human RARa and RARp.10
Despite the expectation of exquisite specificity fostered by the various discrete combinations of RAR and RXR isoforms, these receptors exhibit a great deal of apparent functional redundancy and/or ability to compensate for loss of another. In gene knockout experiments, more than one receptor can perform the same function in vivo, although this may represent an artifact of the knockouts and demonstrate what can happen, not necessarily what does occur.11 Nevertheless, receptor ablation has provided enormous insight into receptor function. Deletion of the RARa gene results in postnatal lethality within 24 h: RARa-null mice represent only 3% of the population by 1 to 2 months of age. Of these, 60% have webbed digits on both fore and hind limbs. A few mice survive 4 to 5 months, but no males are fertile, and all have severe degeneration of the testis germinal epithelium. RARP-null mice have locomotor defects, reminiscent of Parkinson's disease, but are fertile with normal longevity. RARP-null mice have impaired hippocampal synaptic plasticity and compromised short-term learning (as do RXRy-null mice). Also, the P2 isoform of RAR may serve as a tumor suppressor (see below). RARy mutants show growth deficiency (40 to 80% of the weight of the wild-type mice), early lethality (50% dead by 1 to 3 weeks old and <40% surviving by 3 months) and male sterility due to squamous metaplasia of the seminal vesicles and prostate gland. No genitourinary defects occurred in null females, which are fertile. Mice with null mutations in either RXRa or RXRp die between gestational ages 9.5 and 10.5 and display a wide range of abnormalities. Although the direct cause of death appears to be malformation of the placenta, RXR appear necessary for embryonic development before placentation. Mice null in RXRp or RXRy also have locomotor defects and blunted neuro responses, especially related to dopamine signaling.
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