Section I: This section is an introduction to the field of nuclear receptors. A general overview of nuclear receptor-mediated transcriptional regulation is followed by a review of literature on retinoid and thyroid receptor-mediated signaling. Section II: An introduction to NPDC-1 (neural proliferation, differentiation, and control), its discovery and characterization with regards to developmental expression and cellular localization. In addition NPDC-1 has been found to associate with a number of cell cycle regulatory proteins. NPDC-1 is characterized as a regulator of nuclear receptor-mediated transcriptional regulation. NPDC-1 was also demonstrated to be regulated post-transcriptionally through the ubiquitin/proteosome degradation pathway. Section III: Axolotl NPDC-1 (aNPDC-1) was cloned from axolotl brain and analyzed for homology to NPDC-1 from higher vertebrates. The tissue distribution and developmental expression of axolotl NPDC-1 were also examined. Section IV: The axolotl homolog for RAR (aRAR) was isolated from axolotl brain. Axolotl NPDC-1 and aRAR were then examined in a series of assays for interactions. Axolotl NPDC-1 was found to repress transcription mediated by aRAR to a smaller extent than the repression observed in higher vertebrates. The DNA binding of aRAR-RXR was increased in the presence of aNPDC-1 and complex mobility was also observed. The domain of interaction between aNPDC-1, aRAR and hRXR was localized in the amino terminus of aNPDC-1. Axolotl NPDC-1 was also demonstrated to repress proliferation as measured by reduced [3H] thymidine incorporation. Section V: The axolotl homologs of TR and TR (aTR) genes were isolated and utilized in a series of experiments to demonstrate an interaction between aTRs and aNPDC-1. As observed for RE, aNPDC-1 increases the binding of aTR-RXR heterodimer to xDR4, but no change in the mobility of the complex was observed. Interaction between aNPDC-1, aTR and aTR was localized to the amino terminus of aNPDC-1. In contrast to previous observations for other nuclear receptors, aNPDC-1 was found to stimulate transcription mediated by axolotl TRs, suggesting a role for aNPDC-1 in axolotl metamorphosis. Section VI: A summary of data presented in the previous sections as well as a presentation of future directions and a proposed model for NPDC-1 actions in retinoid and thyroid-receptor mediated signaling in axolotl.

<p>Vitamin A and metabolites (retinoids) are crucial for normal epidermal maturation. Physiological effects are mediated by retinoic acid (RA) that activates nuclear retinoic acid receptors (RARs) in complexes with retinoid X receptors (RXRs), resulting in altered gene transcription.</p><p>Psoriasis is a common disease with unknown etiology. Lesions display inflammation, hyperproliferation, and disturbed epidermal maturation. Treatments include topical or oral synthetic retinoids that allegedly bind to and activate the RARs.</p><p>The mRNA expression of retinoid receptors RARα/γ and RXRα was studied in normal and psoriatic skin samples. RARα and RXRα were significantly reduced in psoriatic plaques as compared to non-lesional and normal skin. <i>In situ</i> immunofluorescence detection revealed altered distribution patterns of the receptor proteins in lesional skin. All three receptor proteins were more intensely detected in the lower half of the epidermis but were significantly reduced in the superficial epidermis compared to both normal and non-lesional skin. </p><p>In order to evaluate the retinoid signaling system in psoriatic lesions, we compared the effect of topical RA on the expression of the cellular RA-binding protein II (CRABPII) in psoriatic and normal skin. CRABPII was induced by RA on mRNA and protein level in non-lesional and normal skin but not in lesional skin, where the basal expression of CRABPII was already up-regulated.</p><p>Changes in retinoid signaling during keratinocyte differentiation <i>in vitro </i>were studied by measuring retinoid receptor and RAR-ligand levels<i>.</i> Exposure to differentiation-inducing levels of calcium, phorbol myristate acetate (PMA) or interferon-γ (IFNγ) led to increased RAR-ligand levels but PMA and IFNγ caused receptor protein loss due to increased proteasomal degradation. Since an increased IFNγ level is a hallmark of psoriatic inflammation, this might be a cause of altered retinoid signaling in lesional epidermis.</p><p><i>Conclusion:</i> Keratinocyte differentiation is accompanied by alterations in the retinoid signaling system. In psoriatic lesions, this system appears to be dysfunctioning due to reduced retinoid receptor levels, which might be an important event in the pathogenesis of the disease.</p>

Vitamin A and metabolites (retinoids) are crucial for normal epidermal maturation. Physiological effects are mediated by retinoic acid (RA) that activates nuclear retinoic acid receptors (RARs) in complexes with retinoid X receptors (RXRs), resulting in altered gene transcription. Psoriasis is a common disease with unknown etiology. Lesions display inflammation, hyperproliferation, and disturbed epidermal maturation. Treatments include topical or oral synthetic retinoids that allegedly bind to and activate the RARs. The mRNA expression of retinoid receptors RARα/γ and RXRα was studied in normal and psoriatic skin samples. RARα and RXRα were significantly reduced in psoriatic plaques as compared to non-lesional and normal skin. In situ immunofluorescence detection revealed altered distribution patterns of the receptor proteins in lesional skin. All three receptor proteins were more intensely detected in the lower half of the epidermis but were significantly reduced in the superficial epidermis compared to both normal and non-lesional skin. In order to evaluate the retinoid signaling system in psoriatic lesions, we compared the effect of topical RA on the expression of the cellular RA-binding protein II (CRABPII) in psoriatic and normal skin. CRABPII was induced by RA on mRNA and protein level in non-lesional and normal skin but not in lesional skin, where the basal expression of CRABPII was already up-regulated. Changes in retinoid signaling during keratinocyte differentiation in vitro were studied by measuring retinoid receptor and RAR-ligand levels. Exposure to differentiation-inducing levels of calcium, phorbol myristate acetate (PMA) or interferon-γ (IFNγ) led to increased RAR-ligand levels but PMA and IFNγ caused receptor protein loss due to increased proteasomal degradation. Since an increased IFNγ level is a hallmark of psoriatic inflammation, this might be a cause of altered retinoid signaling in lesional epidermis. Conclusion: Keratinocyte differentiation is accompanied by alterations in the retinoid signaling system. In psoriatic lesions, this system appears to be dysfunctioning due to reduced retinoid receptor levels, which might be an important event in the pathogenesis of the disease.