Site Design and Maintainance,
Nora Edwards
From the Office of Dr. David Crews
Focus of Research
Note: (numbers in parentheses indicate publication number)
5. Directed evolution of the estrogen receptor.
This is new interest that is not as yet supported by external funds. Its genesis is the often-observed fact that some individuals living in polluted areas continue to reproduce successfully, exhibiting resistance to an estrogenic chemical environment. Several mechanisms have been proposed for resistance in wild populations, most involving adaptive responses in catabolism or increased binding proteins to sequester the estrogenic contaminant. Another as yet untested possibility is that the structure and function of the estrogen receptor is changed upon exposure in these individuals. That is, being the product of evolution itself, the estrogen receptor may be capable of evolving the ability to discriminate between endogenous and exogenous estrogens. We presently are examining mutations arising in human estrogen receptor sequence under directed selective pressures in a yeast system.
Figure 1 • Figure 2 • Figure 3
Levels in the organization of sexual behavior. Beginning with a single cell, the zygote, how does variation between the sexes, as well as within each sex, emerge? In mammals and other vertebrates with sex chromosomes, the primary level of organization arises indirectly from the genetic constitution of the individual. The steroid hormones secreted by the gonads organize the differences between the sexes. The secondary level of organization that follows establishes the differences between individuals. Yet the variation within a sex often is greater than the difference between the "average" male and female. The next frontier in behavioral neuroendocrinology will address the relationship between these levels, thereby increasing our understanding of the proximate bases of individual variability.
Different sex determining mechanisms in vertebrates. In genotypic sex determination (top panel), gonadal sex is fixed at fertilization by sex-specific chromosomes and only after the gonad is formed do hormones begin to exert an influence, sculpting specific structures that eventually will differ between the sexes. In environmental sex determination, an individual's gonadal sex is not irrevocably set by the genetic composition inherited at fertilization. Rather, the abiotic or the biotic environment can provide the stimulus to determines an individual's sex. Two forms of environmental sex determination have been studied to date. In many reptiles gonadal sex is not irrevocably set by the genetic composition inherited at fertilization, but rather depends on the temperature of the incubating egg, a process known as temperature-dependent sex determination (middle panel). Incubation temperature modifies the temporal and spatial patterns of expression of genes coding for steroidogenic enzymes and steroid hormone receptors such that sex-specific hormone milieus created in the brain and urogenital system of the developing embryo determine gonad type. Research on hermaphroditic fish reveals a behavior-dependent sex determination mechanism (bottom panel) in which social stimuli encountered by the adult leads to sex change. This change is a neurally-mediated event, where social stimuli modify activity of hypothalamic neurons that produce arginine vasotocin. It is possible that these stimuli also modulate neurons that secrete gonadotropin-releasing hormones which, in turn, act on neurons that project to the gonads. The activity of these neurons modifies the endocrine environment within the gonad by influencing expression of enzymes that code for steroidogenic enzymes, bringing about gonadal transformation.
Evolution of a new neuroendocrine system. Shown is the relation among male-like and female-like pseudosexual behavior, ovarian state and circulating levels of estradiol and progesterone during different stages of the reproductive cycle of the parthenogenetic whiptail lizard. The transition from receptive to mounting behavior occurs at the time of ovulation (arrow). Also shown are the changes in estrogen receptor (ER)- and progesterone receptor (PR)-mRNA concentration in the preoptic area (POA) and the ventromedial hypothalamus (VMH). Not shown are changes in volume of these brain areas, which do not change throughout different phases of the physiological and behavioral cycles.
