Timing is key

For many important events, tests, and aspects of our lives we rely on time. Without proper timing we may not arrive on time to a special event or finish a test that could dictate our career. Like how we rely on the time on the clock our bodies rely on a biological timer to determine when we will experience puberty. The timing cues we receive from specific genes in our bodies indicate when hormones are released, and the body begins to change. By focusing on a shared gene between humans and the small worm, C. elegans, researchers have come to learn more about the biological clocks between different organisms.

The sexual development between mammals and C. elegans is very different. Mammals undergo sexual maturation through the release of hormones from their sexual reproductive organs. These hormones are released based on a developmental schedule in the body controlled by the gene Makorin3 (MKRN3) and the miRNA regulators LIN28A/B. The hormones are then released through the hypothalamus within the brain and influences the changes within the body. On the other hand, C. elegans do not undergo sexual maturation due to hormone release. Instead sexual maturation relies on functional changes of neurons which then influence the nervous system; the changes are independent of the gonads. New neurons are formed during the larval stages of development and lead to copulation structures and egg laying behavior. The maturation C. elegans undergo then changes their sexual behaviors and how they interact with the opposite sex, specifically for the male worms. Although both types of organisms experience dramatically different sexual maturation events, they both proceed based on a schedule. Surprisingly, the gene Makorin3 is also found in the C. elegans, indicating a conserved sequence between the two organisms.

To begin to understand the molecular mechanisms of maturation in C. elegans we must focus on the behavioral aspects and the larval stages at first. Although both sexes (male and hermaphrodites) of the worms experience sexual maturation, the male sex undergoes more noticeable changes in behavior. Once male worms proceed into adulthood, they begin to search for hermaphrodite worms in their vicinity. To prevent themselves from starving they will leave food behind and search for a mate around that area. Once a mate is found, males will proceed to undergo a series of steps to mate. These steps include sliding along the hermaphrodite’s body, searching for the vulva and copulation. Only after sexual maturation has occurred will males have this behavior.

Both male and hermaphrodite worms experience four larval stages until adulthood. These stages are known as L1, L2, L3 and L4, with L4 being the final stage. During the L3 stage male worms will begin to undergo a functional change within their neurons; dictating male specific behavior later. By L4 the nervous system in both sexes has been established and the sex specific behavior has been determined.

The work published by Dr. Hannah Lawson and colleagues from the University of Rochester in the journal eLIFE provided insight into the timing mechanisms seen in mammals and C. elegans. By focusing on the Makorin3 gene and the genes lep-2, lep-5, and lin-28 found in C. elegans Dr. Hannah Lawson was able to determine the purpose of these genes within the worm’s sexual maturation schedule.

A pathway known as the heterochronic pathway has been found to be involved in the scheduling of sexual maturation in C. elegans. The heterochronic pathway is a complex mechanism that controls the steps of proliferation and differentiation in seam cells. Seam cells are skin like cells that are found along the sides of the body. The pathway regulates each transition from one event to the next during maturation; determining when a change of function occurs within a neuron. The genes involved in this mechanism are what regulate and control the timing of sexual maturation. As mentioned previously the genes Dr. Hannah Lawson focused on MKRN3, lep-2, lep-5 and lin-28. Each of these genes contributed to the heterochronic timing, either inhibiting or promoting the maturation process.

Through a series of experiments using male worms lacking or overexpressing each of these genes, the Lawson lab was able to determine the purpose of each gene. Mutant worms overexpressing the MKRN3 gene showed a delay in sexual maturation indicating the gene’s importance in timing. As shown in previous studies, the MKRN3 gene has also been found in the timing of mammal sexual maturation. Because this gene also has an influence on the C. elegans maturation, this gene sequence is conserved between the organisms. After testing males lacking the lep-5 and lep-2 genes, the researchers noticed that male specific behavior, such as the food leaving behavior and vulva location, was severely decreased or almost completely absent. Because these two behaviors are essential for proper male mating behavior, lep-2 and lep-5 were then determined to have a significant effect on the timing of male sexual drive. In short, these two genes are maturation promoting. Mutant male worms lacking the lin-28 gene showed indications of late sexual maturation occurring earlier than expected. The precocious behavior observed represents the importance of lin-28 in inhibiting maturation from occurring too early. Through a carefully timed pathway and the specific order of genes, the proper sexual maturation can occur.

Based on the results collected by the Lawson lab, the researchers have predicted that the heterochronic timer found in C. elegans is an ancient regulator of sexual maturation. The Makorin3 gene can be found in both C. elegans and mammals, indicating that the gene sequence has been conserved between the organisms. As a result of a recent evolutionary adaptation, the mammal sexual maturation timer may have resulted in a dependence on gonad releasing hormonal signals.

The work of Dr. Hannah Lawson and colleagues resulted in an insightful discovery on sexual maturation. Through thorough analysis of the genes found in the heterochronic pathway they were able to determine the function of these genes and how they interact with each other. Not only do these results show significant progress for understanding C. elegans sexual maturation, but also the relationship between mammals and simpler organisms.