Hall worked primarily with
Drosophila to study the mechanism of
circadian rhythms. Rather than using the more traditional method of measuring
eclosion, Hall measured locomotor activity of
Drosophila to observe circadian rhythms.
Discovery of PER protein self regulation In 1990, while in collaboration with
Michael Rosbash and Paul Hardin, Hall discovered that the Period protein (PER) played a role in suppressing its own transcription. While the exact role of PER was unknown, Hall, Rosbash, and Hardin were able to develop a negative transcription-translation feedback loop model (
TTFL) that serves as a central mechanism of the circadian clock in
Drosophila. In this original model,
per expression led to an increase of PER. After a certain concentration of PER, the expression of
per decreased, causing PER levels to decrease, once again allowing
per to be expressed.
Discovery of synchronization between cells In 1997, Hall was a part of group with Susan Renn, Jae Park, Michael Rosbash, and Paul Taghert that discovered
genes that are a part of the TTFL are expressed in cells throughout the body. Despite these genes being identified as necessary genes to the circadian clock, there was a variety of levels of expressions in various parts of the body; this variation was observed on the cellular level. Hall succeeded in entraining separate tissues to different light-dark cycles at the same time. Hall didn't discover the element that synchronizes cells until 2003. He found that the
pigment dispersing factor protein (PDF) helps control the circadian rhythms, and in turn
locomotor activity, of these genes in cells. This was localized to small
ventral lateral neurons (sLNvs) in the Drosophila
brain. From this data, Hall concluded the sLNvs serve as the primary oscillator in Drosophila and PDF allows for synchrony between cells. He was awarded the 2017 Nobel Prize in Medicine or Physiology.
Refining the transcription-translation negative feedback loop model In 1998, Hall contributed to two discoveries in
Drosophila that refined the TTFL model. The first discovery involved the role
Cryptochrome (CRY) plays in entrainment. Hall found that CRY is a key photoreceptor for both entrainment and regulation of locomotor activity. He hypothesized CRY may not be just an input to the circadian system, but also a role as a pacemaker itself. In the same year, Hall discovered how the Drosophila
per and
timeless (
tim) circadian genes were regulated. Hall discovered that
CLOCK and
Cycle (CYC) proteins form a heterodimer via the
PAS domain. Upon dimerizing, the two proteins bind to the
E box promoter element of the two genes via the
bHLH domain to induce expression of
per and
tim mRNA. ==References==