The Attractin Gene

This week, I have completed my research paper, although, as I have been organizing my extensive research into the paper, I have thought of various questions that I will discuss with my lab mentors. I will also be working on my presentation more this week. I further completed statistical analysis of my data and am gaining an understanding of how to appropriately interpret and communicate my results. Thus, I am continuing to gain valuable skills to apply to any research.

In addition to the implications of my research in supporting the presence natural selection, the results of my research have numerous medical applications. Both the agouti and attractin gene, which are currently being studied regarding their involvement in the pigmentation pathway, have numerous pleiotropic effects throughout the body. Agouti effects numerous tissues, especially due to ectopic expression in the hypothalamus; for instance, production of eumelanin (dark pigment) may shield the skin from ultraviolet radiation, while the Agouti-induced production of pheomelanin may lead to the production of free radicals that cause carcinogenesis. Additionally, Agouti, especially when overexpressed in the wrong regions of the body (ectopically overexpressed) in the lethal yellow mouse, causes adult-onset obesity, insulin-resistant diabetes, hyperleptinemia (increased levels of serum leptin, a peptide [amino acid chain] hormone neurotransmitter produced by fat cells and involved in appetite), increased linear growth, higher tumor susceptibility, hyperphagia (increased appetite), hyperglycemia (high levels of blood glucose), and infertility. Dominant mutations in Agouti further result in neurological defects, hyperinsulinemia, coronary heart disease, and other fatal or debilitating ailments in many mammals, including humans. Agouti has also been implicated in controlling influx and efflux of Ca+2, which plays a significant role in signal-transduction, and thus influences hormone secretion, neurotransmitter release, enzyme and ion channel activity, gene expression, mitosis and meiosis, apoptosis, and possibly insulin-mediated glucose transport, resulting in obesity and diabetes. The mechanisms for these many pleiotropic effects of Agouti are uncertain; however, some research suggests that the receptor to which Agouti binds is expressed in nonpigmentated tissue or that Agouti can bind to a family of receptors (Miller et al. 1993).

The Attractin gene further has numerous pleiotropic effects beyond the pigmentation pathway. Attractin likely has an independent role in the brain. Attractin also influences the development and function of the central nervous system. The structure of Attractin suggests its involvement in cell adhesion or axon (a nerve fiber that conducts impulses away from the nerve cell) guidance. Homozygosity (two of the same allele [version of a gene]) for Atrnmg-3J results in vacuolation (becoming filled with cavities) of the brain and spinal cord; furthermore, an autosomal (non-sex cell) recessive loss-of-function mutation in Attractin (Atrnzi), which decreases the amount of Attractin mRNA in the brain, results in the phenotype of the zitter rat, which has spongy degeneration, increased oxidative stress (the release of free radicals, causing cellular degeneration), apoptosis leading to neuronal cell death, and hypomyelination (defective formation of myelin, a fatty lipid that encloses axons and nerve fibers, in the spinal cord and brain)in the central nervous system that causes tremor, abnormal auditory brainstem responses (to sound), and flaccid paresis (loss of muscle tone due to injury of the nerves) of the hind limbs. A major function of Attractin is likely to maintain cell-cell interactions, and, when this function is not performed, vacuolation of the central nervous system takes place. The Attractin gene likely has a significant role in body weight regulation both influenced by and independent of Agouti and likely plays a role in regulating cellular response to neurotoxins, even protecting against certain toxins through mitochondrial functions. The soluble Attractin found in humans and rats may be involved in immune cell interactions. Thus, Attractin mutations cause pleiotropic effects of dark coat, juvenile-onset neurodegeration, hypomyelination, split myelin sheaths (lipid and lipoprotein structures, which surround a nerve fiber or axon and aid in the transmission of nerve impulses), axonal swelling, hyperactivity, and progressive vacuolation and tremor, causing increased energy expenditure, and altered immune response. Additionally, neurodegeneration in Attractin mutant mice is likely the cause of abnormal behavior, increased movement, and decreased lean body mass. Still, the mechanisms for these pleiotropic effects, as well as for Attractin’s interaction with Agouti, are unclear. Therefore, my research studying the Attractin gene and its relation to the Agouti gene, beyond adding to a growing understanding of the process of evolution, has a potential role for therapeutic and preventative intervention in human disease.