Department of Biology

Jeffrey Hall

Professor Emeritus of Biology

Jeffrey Hall, along with Michael Rosbash (Brandeis University), and Michael Young (Rockefeller University) received the Nobel Prize in Physiology or Medicine in 2017. 

Research Description

Hall and his colleagues investigated the function of the nervous system in Drosophila. Many of their approaches involved genetic studies of behavior, augmented by molecular manipulations of genes defined by certain behavioral mutations.

These investigations were in two areas: molecular neurogenetics of courtship and molecular neurogenetics of biological rhythms. 

Molecular Neurogenetics of Courtship

How is Drosophila's central nervous system programmed to control elements of the flies' reproductive behaviors? Our earlier studies that addressed this question involved identification of pertinent portions of the adult CNS, using "sex mosaics" and disruptions of these tissues, using mutants specifically defective in the metabolism of a centrally acting neurotransmitter, acetylcholine.

We then focused most of our attention on courtship mutants. One is defined by genetic changes at the fruitless (fru) locus, which cause males not to mate with females and anomalously to court other males. The genetics of fru are as complicated as the syndrome of behavioral abnormalities. We hoped to unravel some of these complexities by virtue identifying the fru at the molecular level. These and other neurobiological findings on the fru gene and its mutants have led to the demonstration that this factor acts within Drosophila's "sex-determination hierarchy" (SDH) and defines a new branch of it. In this context, fru, like certain other SDH genes, encodes a transcription factor. We discovered that production of serotonin (5HT), in certain of the many neurons that express male-specific forms of FRU protein, is regulated by the action of this gene. Moreover, the 5HT neuromodulator seems to regulate functions of male reproductive organs, which are dramatically perturbed in certain fru mutants.

Two other courtship mutants were isolated because of abnormal male "singing" behavior: cacophony (cac) and dissonance (diss) males generate aberrant sounds from the wing vibrations they direct at females. To approach an understanding of how these species-specific courtship songs are programmed into the fly, we carried out high resolution analyses of mutant vs. normal sounds. Genetic studies of the cac and diss loci implied complexities analogous to those associated with fru. For example, complementation analyses and molecular expression assessments indicate that both song genes are involved in the control of visually mediated responses made by the adult fly (as monitored behaviorally and physiologically). The cac gene encodes a voltage-regulated calcium channel (a1 subunit). This rationalizes at least the courtship-song defect in the cac mutant. The diss mutation is a variant of the nonA gene, which was defined originally by visual mutants and encodes an RNA-binding protein (NONA). We hypothesized that NONA influences post-transcriptional processing of the primary cac transcript. Indeed, there are several different isoforms of that mRNA, resulting from alternative splicing and RNA editing.

The rate at which Drosophila males generate the "tone pulse" components of their courtship song varies rhythmically. The cycle durations are short, ranging from about a half-minute to a minute-and-a-half, depending on the species. In one of these, D. melanogaster, circadian rhythm mutations at the period (per) locus cause song rhythm abnormalities that parallel the defects in "daily" rhythm phenotypes. These song findings provided entrées into our more extensive studies of biological rhythms.

Molecular Neurogenetics of Biological Rhythms

We initiated molecular studies of circadian rhythms by analyzing the per gene, in collaboration with Michael Rosbash at Brandeis University. Through the 1990s, these investigations expanded to molecular and neurobiological experiments revolving round five additional rhythm-related genes in Drosophila, which were either cloned by others [timeless (tim)] or by us [Clock (Clk), cycle (cyc), and cryptochrome (cry), and pigment-dispersing factor (pdf)]. The various molecular-neuro-chronobiological investigations have involved:

• determination and manipulation (for bioasssays) of these genes' informational content
• in-vitro manipulations of clock genes or portions thereof--aimed in part at assessing the expression patterns of these genes at different stages of the life cycle and in a variety of neural and non-neural tissues; these studies included experimental identification of the neuronal pacemaker cells underlying the fly's behavioral circadian rhythms
• studies of environmental inputs to the circadian pacemaker, as mediated in part by cry function (which may be principally concerned with blue-light reception, but also seems connected to actual pacemaker operation), and probably by Clk and cyc as well (these are mainly clock factors, but the mutants also exhibit abnormal light-responsiveness in the context of daily rest-activity rhythms)
• manipulation of the pdf gene, which in Drosophila does not encode literally a pigment-dispersing factor--instead, an oligopeptide found only in the CNS; these experiments showed (to a first approximation) how PDF participates in output functions of the circadian clock, those underlying the flies' sleep-wake cycles
• comparison of the structure and function of clock genes in closely vs. distantly related Drosophila species; these data have revealed, for example that certain coding regions are highly conserved and others very diverged, among the different species; such findings led to interspecific transfer experiments, in which the effects of all or part of a donor species' per gene have been bioassayed in D. melanogaster hosts.

To identify additional clock-related genes that contribute to the overall mechanism of circadian pacemaking, we searched for new rhythm variants. One way of detecting such factors involved testing flies carrying transgenes in which we fused parts of clock genes to a reporter factor--firefly luciferase (luc). This allowed per- and tim-controlled molecular rhythms to be tracked in real time, in flies that are individually monitored for "glow cycling" over the course of several days. The initial fruits of luc-based screening for molecularly defective rhythm variants included two new mutations at the tim locus (which confirmed the validity of this approach) and genetic identification of a novel chronobiological factor, cry.