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Leigh Wexler Graduates!

Friday, September 6, 2019

quiet time

Dr. Leigh Wexler and Dr. Portman (From Left)

Congratulations to Dr. Leigh Wexler, who successfully defended their thesis this week, earning a Ph.D. in Genetics from the GDSC program. Leigh’s thesis research in the Portman Lab focused on the regulation of neuronal circuit function and behavior in the nematode C. elegans. It’s been known for many years that males of this species tend to leave a food source to find mates, but that depriving males of food causes them to reprioritize feeding behavior over exploration. One important component of this behavioral flexibility is regulated chemosensory function. Well-fed males detect food poorly, partly due to low expression of a food-associated chemoreceptor called ODR-10, but food-deprived males upregulate ODR-10, increasing food attraction and decreasing food-leaving behavior. In contrast, hermaphrodites (the female equivalent in C. elegans) are strongly attracted to food and exhibit high levels of ODR-10 expression even when well-fed.

Leigh’s research probed the mechanism by which ODR-10 expression is influenced by feeding status in males. They found that signals through two conserved pathways, involving the TGFβ-family ligand DAF-7 and the insulin-like (IIS) receptor DAF-2, are important for keeping ODR-10 expression low in well-fed males. Further, Leigh found that males in which the IIS pathway is constitutively active fail to upregulate ODR-10 when starved. Interestingly, the DAF-7 signal appears to act upstream of IIS, indicating that a cascade of neuroendocrine interactions is necessary for repressing ODR-10. And DAF-7 does not act as a sensor of the starved male’s physiological state, but rather conveys information about the presence of food in the environment.

Together, Leigh’s research demonstrates that C. elegans males assess their external state, rather than their metabolism, when deciding whether to take the risk of leaving food to find a mate, and that this occurs through a multistep neuroendocrine feedback loop. Leigh’s work also provides important insights into how internal and external states are integrated by the nervous system to influence gene expression, neuronal circuit function, and behavior. This work will appear in an upcoming issue of Current Biology. We wish Leigh all the best as she set out to Boston, to start her post-doctoral career in the laboratory of Max Heiman at Harvard.

Studies Led by Douglas Portman Examine Nervous System Changes During Puberty

Tuesday, July 9, 2019

Very little is known about how the onset of puberty is controlled in humans, but the discovery of a new gene in the roundworm C. elegans could be the "missing link" that determines when it’s time to make this juvenile-to-adult transition. Two genes, LIN28and MKRN3, are known to be associated with precocious puberty in humans, where juveniles as young as six may start developing adult features. These genes are found in all animals, including C. elegans, in which they also control the juvenile-to-adult transition. Until the new discovery, it was unclear how these two genes are connected.

The more obvious signs of the transition of juvenile-to-adult tend to be external—body morphology, matured genitalia—but nervous system changes are also happening at the same time. In humans, the maturation of the brain during adolescence is associated with increased vulnerability to a variety of neuropsychiatric disorders, so a better understanding of these processes is important for understanding mental health as well as basic neurobiology.

Two new studies in the labs of Douglas Portman, Ph.D. at the University of Rochester Medical Center and David Fitch at New York University, published in Developmental Cell and eLife, identified a new developmental timing mechanism involving a long non-coding RNA in the microscopic roundworm C. elegans. Their research revealed a surprising new molecular mechanism that controls the timing of sex-specific changes in body shape, the maturation of neural circuits, and behavior.

C. elegans has long been used by researchers to understand fundamental mechanisms in biology. Many of the discoveries made using these worms apply throughout the animal kingdom and this research has led to a broader understanding of human biology. In fact, three Nobel Prizes in medicine and chemistry have been awarded for discoveries involving C. elegans.  

The researchers identified a new gene that, when disrupted, delays the transition from the juvenile to the adult stage. Surprisingly, this gene, called lep-5, does not act as a protein, as most genes do. Instead, it functions as a long non-coding RNA (lncRNA), a recently discovered class of genes whose functions remain largely mysterious. The team observed that this lncRNA is important for promoting the juvenile-to-adult transition by directly interacting with LIN-28 and LEP-2, a C. elegans gene similar to MKRN3. Because the human versions of LEP-2 and LIN-28 are both involved in the timing of puberty, the new research suggests that a yet-to-be-discovered lncRNA might be essential to this process in humans as well.

Read More: Studies Led by Douglas Portman Examine Nervous System Changes During Puberty