RICHARD PALMITER
Howard Hughes Medical Institute, University of Washington, Seattle WA
Functional Genomics
There are numerous ways to identify interesting genes. Traditionally, one identified a
protein first and then used information about it to identify the corresponding gene.
Members of gene families were often found by cross-hybridization techniques. Other
methods for identifying genes based on their properties include: knock-down (RNAi)
strategies, gene traps, positional cloning, micro-array analysis, and protein-protein
interaction strategies (2-hybrid & pull-down applications). The availability of the genome
sequence for many organisms, has simplified characterization of the gene structure and
there are now numerous was to examine mRNA processing and expression. Despite all
of these advances, determining gene function still requires extensive knowledge of
biological systems and tools to manipulate expression of select genes in genome wide,
cell-specific, and/or a temporal manner.
Our laboratory is primarily interested in how neurotransmitters regulate development,
physiology and behavior. Our primary tool is to genetically modify mouse genes
responsible for neurotransmitter biosynthesis as a first step in understanding what
processes depend on a particular gene. The next step often entails either conditional
inactivation in selected neurons, or selective restoration of neurotransmitter synthesis to
particular brain regions using viral gene therapy strategies. The next frontier involves
gaining temporal control over when a particular gene is inactivated.
I will illustrate the use of some of these tools as applied to mice with knockout of
neuropeptide Y (Npy), tyrosine hydroxylase (Th) or dopamine -hydroxylase (Dbh)
genes as examples. We have been studying the consequences inactivating these three
genes for over 10 years now and still have a lot to learn about the many functions of
their gene products.
Neuropeptide Y
Erickson, J.C., Clegg, K.E. and Palmiter, R.D. (1996) Sensitivity to Leptin and
Susceptibility to Seizures of Mice Lacking Neuropeptide Y. Nature 381, 415-418.
Luquet, S., Perez, F.A., Hnasko, T.S. and Palmiter, R.D. (2005) NPY/AgRP Neurons Are
Essential for Feeding in Adult Mice but Can Be Ablated in Neonates. Science 310,
683-685.
Tyrosine hydroxylase
Zhou, Q-Y and Palmiter R.D. (1995) Dopamine-deficient Mice Are Severely Hypoactive,
Adipsic and Aphagic. Cell 83, 1197-1209.
Szczypka, M.S., Kwok, K., Brot, M.D., Marck, B.T., Matsumoto, A.M., Donahue, B.A. and
Palmiter, R.D. (2001) Dopamine Production in the Caudate Putamen Restores
Feeding in Dopamine-deficient Mice. Neuron 30, 819-828.
Dopamine beta-hydroxylase
Thomas, S. A., Matsumoto, A.M. and Palmiter, R.D. (1995) Norepinephrine is Essential
for Mouse Development. Nature 374, 643-646.
Thomas, T.A and Palmiter, R.D. (1997) Impaired Maternal Behavior in Mice Lacking
Norepinephrine and Epinephrine. Cell 91, 583-592.