Readers, S.T. 1992. Molecular genetics of heredi- 
tary nephritis. Kidney Int 42:783-792. 
Readers, S.T. 1992. Multilocus polycystic disease. 
Nature Genet 1:235-237. 
Somlo, S., Germino, G.G., Wirth, B., Weinstat- 
Saslow, D., Barton, N., Gillespie, G.A.J. , Fris- 
chauf, A. M., and Reeders, S.T. 1992. The molec- 
ular genetics of autosomal-dominant polycystic 
kidney disease of the PKDl type. Contrib 
Nephrol 97:101-109. 
Somlo, S., Wirth, B., Germino, G.G., Weinstat- 
Saslow, D., Gillespie, G.A.J. , Himmelbauer, H., 
Steevens, L., Coucke, P., Willems, P., Bachner, L., 
Goto, E., Lopez-Larrea, C., Peral, B., San Mi- 
llan, J.L., Lavinha, J., Saris, J.J., Breuning, M.H., 
Frischauf, A.-M., and Reeders, S.T. 1992. Fine ge- 
netic localization of the gene for autosomal domi- 
nant polycystic kidney disease (PKDl) with re- 
spect to physically mapped markers. Genomics 
13:152-158. 
MOLECULAR GENETICS OF RNA PROCESSING AND CIRCADIAN RHYTHMS 
Michael Rosbash, Ph.D., Investigator 
Dr. Rosbash's laboratory has been engaged for 
some time in two different areas of investigation. 
The first is RNA processing and the second is circa- 
dian rhythms. The common thread is the approach, 
which emphasizes conventional and molecular 
genetics. 
RNA Processing 
The two post-transcriptional events of interest to 
Dr. Rosbash and his colleagues are pre-mRNA splic- 
ing and transport of mRNA from the nucleus to the 
cytoplasm. There is evidence to suggest that these 
two processes are competing — i.e., assembly of a 
pre-mRNA transcript into a splicing complex pre- 
vents RNA transport to the cytoplasm until splicing 
is successful. As a consequence, both nuclear reten- 
tion as well as RNA transport must be studied to 
understand the flow of information from nucleus to 
cytoplasm. 
There is considerable evidence that the REV gene 
product of the human immunodeficiency virus 
(HIV) promotes transport of unspliced, or partially 
spliced, viral RNA to the cytoplasm. It has proved 
difficult to ascertain whether REV functions by ac- 
tively promoting RNA transport or by inhibiting the 
nuclear retention normally afforded by the splicing 
machinery. To distinguish between these two possi- 
bilities, Dr. Rosbash and his colleagues are attempt- 
ing to recapitulate the REV system in yeast so that 
genetic methods can be used to identify the proteins 
with which it interacts. They are also working with 
several yeast mutants that appear to perturb the nor- 
mal transport of mRNA from nucleus to cytoplasm. 
Of most interest at present is the gene PRP20. Its 
characteristics and its mammalian relatives suggest a 
connection between transcription on the one hand 
and RNA transpon on the other. This connection be- 
tween splicing and RNA processing is reinforced by 
biochemical approaches, which indicate that pre- 
mRNA splicing in yeast takes place on nascent 
transcripts. This has significant implications for 
cell biological experiments that localize splicing 
components to subnuclear domains in both yeast 
and mammalian cells. 
A second RNA-processing project is focused on 
the more biological events of pre-mRNA splicing — 
namely, those associated with splice site recogni- 
tion. A major problem in splicing is how splice sites 
are recognized and how splice site partners are as- 
signed, e.g., which 5' site will be attached to which 
3' site. In vivo experiments indicate that noncon- 
served sequences within the pre-mRNA are impor- 
tant for splice site partner assignment. Experiments 
in progress are designed to define the biochemical 
mechanism responsible for this role of noncon- 
served sequences. 
It is also known that Ul snRNP (small nuclear 
ribonucleoprotein) is very important in these early 
events of intron recognition. It is the first splicing 
component to interact with the pre-mRNA during in 
vitro assembly of the spliceosome, the large com- 
plex within which the cleavage and ligation events 
of splicing take place. The Rosbash laboratory is 
currently engaged in both biochemical and genetic 
experiments designed to further understanding of 
the role of Ul snRNP and its interaction with the 
pre-mRNA substrate. These experiments are also be- 
ginning to identify the protein components of yeast 
Ul snRNP, most of which remain undefined. (This 
project was supported by a grant from the National 
Institutes of Health.) 
Circadian Rhythms 
The other major interest of Dr. Rosbash and his 
colleagues is circadian rhythms. To understand the 
biochemical mechanisms that underlie biological 
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