In Drosophila, like in humans, male cells have a single X chromosome, while female cells have two. Researchers have long debated over how X and autosomal chromosome gene expression is equalized between the sexes (generally regarding two different models, known as the activation model and the inverse model). These two papers provide the first definitive in vivo evidence in favor of the activation model of dosage compensation in flies.
The male-specific-lethal (MSL) complex functions as a male-specific regulatory protein complex that controls gene expression in male fruit fly cells. The activation model proposes that MSL upregulates the transcription of X-linked genes twofold in male cells. The inverse dosage effect model proposes that MSL represses male autosomal gene expression to balance gene expression.
The Becker and Kuroda labs both utilized RNAi technology to analyze the effects of decreased MSL expression. Using different, yet complementary, experimental systems, both found that MSL downregulation results in reduced expression of most X-linked genes, while not affecting autosomal gene expression levels. These results clarify the role of MSL as a specific activator of X-linked gene expression, and that dosage compensation occurs by a twofold upregulation of the single X chromosome in male fly cells.
Dr. Becker states that "The clear-cut result we obtained clarifies this controversial issue at least to our satisfaction. How the different components of the male-specific lethal complex contribute to fine-tuning of gene expression in a two-fold range remains an interesting challenge for future studies."
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CART peptides may also hold promise as a therapeutic target for treating obesity. Early rodent studies showed a potent suppression of eating when CART peptides were injected directly into the brain. These studies suggested a role for CART peptides in the motivation or reason for why one eats. Interestingly, appetite suppression produced by CART peptide injections is similar to that seen with cocaine and amphetamine use. The precise mechanism by which cocaine and amphetamine decrease weight remains unknown, but CART peptides may have a role here as well. Future studies are needed to investigate the role of CART peptides in eating and obesity.
These findings point to a novel target for treating stimulant drug addiction. Selective drugs can be developed that may suppress the action of natural CART peptides to blunt the 'high' produced by addictive drugs. This may be a useful strategy for preventing drug relapse. The unique location of CART peptides within subsections of the brain involved in pleasure and emotions suggest that selective drugs may be developed with minimal side-effects. At a minimum, CART peptides represent a new strategy in the struggle to develop treatments for cocaine and amphetamine drug addiction.
These research findings are published in the manuscript "CART Peptides Modulate the Locomotor and Motivational Properties of Psychostimulants" by Pastor R. Couceyro, Charity Evans, Audra McKinzie, Darrion Mitchell, Matt Dube, Leila Hagshenas, Francis J. White, Jim Douglass, William G. Richards, and Anthony W. Bannon. Dr. Couceyro is Assistant Professor of Cellular and Molecular Pharmacology, and Dr. White is Professor of Cellular and Molecular Pharmacology at Rosalind Franklin University of Medicine and Science (RFUMS). Ms. Evans, Mr. Mitchell, Mr. Dube, and Ms. Hagshenas are students at RFUMS. Ms. McKinzie, Dr. Douglass, Dr. Richards and Dr. Bannon are collaborating researchers at Amgen Inc. The manuscript is available online at jpet.aspetjournals/cgi/reprint/jpet.105.091678v1 and will appear in the Journal of Pharmacology and Experimental Therapeutics later this year.
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