ABSTRACT
The prefrontal cortex (PFC) and its connections with the mediodorsal thalamus are crucial for cognitive flexibility and working memory1 and are thought to be altered in disorders such as autism2,3 and schizophrenia4,5. Although developmental mechanisms that govern the regional patterning of the cerebral cortex have been characterized in rodents6-9, the mechanisms that underlie the development of PFC-mediodorsal thalamus connectivity and the lateral expansion of the PFC with a distinct granular layer 4 in primates10,11 remain unknown. Here we report an anterior (frontal) to posterior (temporal), PFC-enriched gradient of retinoic acid, a signalling molecule that regulates neural development and function12-15, and we identify genes that are regulated by retinoic acid in the neocortex of humans and macaques at the early and middle stages of fetal development. We observed several potential sources of retinoic acid, including the expression and cortical expansion of retinoic-acid-synthesizing enzymes specifically in primates as compared to mice. Furthermore, retinoic acid signalling is largely confined to the prospective PFC by CYP26B1, a retinoic-acid-catabolizing enzyme, which is upregulated in the prospective motor cortex. Genetic deletions in mice revealed that retinoic acid signalling through the retinoic acid receptors RXRG and RARB, as well as CYP26B1-dependent catabolism, are involved in proper molecular patterning of prefrontal and motor areas, development of PFC-mediodorsal thalamus connectivity, intra-PFC dendritic spinogenesis and expression of the layer 4 marker RORB. Together, these findings show that retinoic acid signalling has a critical role in the development of the PFC and, potentially, in its evolutionary expansion.
Subject(s)
Organogenesis , Prefrontal Cortex/embryology , Prefrontal Cortex/metabolism , Tretinoin/metabolism , Animals , Axons/metabolism , Cerebral Cortex , Down-Regulation , Female , Humans , Macaca mulatta , Male , Mice , Pan troglodytes , Prefrontal Cortex/anatomy & histology , Prefrontal Cortex/cytology , Receptors, Retinoic Acid/deficiency , Retinoid X Receptor gamma/deficiency , Signal Transduction , Synapses/metabolism , Thalamus/anatomy & histology , Thalamus/cytology , Thalamus/metabolismABSTRACT
Retinoid and rexinoid receptors are known to regulate key processes during development, differentiation, and cell death in vertebrates. However, their contributions to progression of malignant disease remain largely elusive although it is realized that transformed cancer cells, which essentially evade apoptosis, may display altered molecular expressions or functions associated with retinoid signaling. Here, using a progression model of ovarian cancer, we describe a proteomics-based approach including experimental procedures toward identification and validation of altered protein profiles during transformation. Effectively, this specifies loss of RXR-γ during progression of epithelial ovarian cancer.
Subject(s)
Carcinoma, Ovarian Epithelial/pathology , Ovarian Neoplasms/pathology , Proteomics/methods , Retinoid X Receptor gamma/deficiency , Animals , Carcinoma, Ovarian Epithelial/metabolism , Cell Line, Tumor , Disease Progression , Electrophoresis, Gel, Two-Dimensional , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Neoplasm Transplantation , Ovarian Neoplasms/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
Retinoids have been implicated as pharmacological agents for the prevention and treatment of various types of cancers, including breast cancers. We analyzed 27 newly synthesized retinoids for their bioactivity on breast, liver, and colon cancer cells. Majority of the retinoids demonstrated selective bioactivity on breast cancer cells. Retinoid 17 had a significant inhibitory activity (IC50 3.5 µM) only on breast cancer cells while no growth inhibition observed with liver and colon cancer cells. The breast cancer selective growth inhibitory action by retinoid 17 was defined as p21-dependent cell death, reminiscent of senescence, which is an indicator of targeted receptor mediated bioactivity. A comparative analysis of retinoid receptor gene expression levels in different breast cancer cells and IC50 values of 17 indicated the involvement of Retinoid X receptors in the cytotoxic bioactivity of retinoid 17 in the senescence associated cell death. Furthermore, siRNA knockdown studies with RXRγ induced decrease in cell proliferation. Therefore, we suggest that retinoid derivatives that target RXRγ, can be considered for breast cancer therapies.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Cellular Senescence/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Retinoids/chemistry , Retinoids/pharmacology , Antineoplastic Agents/metabolism , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Knockdown Techniques , Humans , Molecular Docking Simulation , Protein Conformation , Receptors, Retinoic Acid/metabolism , Retinoid X Receptor alpha/deficiency , Retinoid X Receptor alpha/genetics , Retinoid X Receptor gamma/chemistry , Retinoid X Receptor gamma/deficiency , Retinoid X Receptor gamma/genetics , Retinoid X Receptor gamma/metabolism , Retinoids/metabolismABSTRACT
Abnormal signaling by retinoids or n-3 polyunsaturated fatty acids has been implicated in clinical depression. The converging point in activities of these two classes of molecules is transcriptional activation of retinoid X receptors (Rxr). We show here that ablation of Rxrgamma in mice leads to depressive-like behaviors including increased despair and anhedonia, which were accompanied by reduced expression of dopamine D2 receptor in the shell of nucleus accumbens (NAc) and altered serotonin signaling. While abnormal serotonin signaling is not sufficient to generate the depressive behaviors, increasing D2r expression by chronic fluoxetine (Prozac) treatment or adenoassociated virus type2 (AAV2) mediated expression of Rxrgamma or D2r in the NAc of Rxrgamma(-/-) mice normalizes depressive-like behaviors in Rxrgamma(-/-) animals. Conversely, NAc infusion of raclopride, a D2r antagonist prevents AAV2-Rxrgamma-mediated rescue of despair behaviors in Rxrgamma(-/-) mice. Combined, our data argue that control of NAc D2r expression is critical for Rxrgamma-mediated modulation of affective behaviors.
