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Michael Nitabach Assistant Professor
of Cellular & Molecular Physiology
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J.D. 1998 New York University -
Ph.D.
1995 Columbia University -
B.A. 1988 University of Pennsylvania
| "Genes, Clocks, and Neurons: Molecular
Genetics and Systems Physiology of Animal Behavior" In
my laboratory, we use techniques drawn from ion channel biology and behavioral
genetics to bridge our understanding of how genes control behavior and how neural
circuits control behavior. In particular, we are interested in the following fundamental
questions: How do the genetic regulatory systems that drive behavior modulate
neuronal membrane properties and the physiology of neural networks? How do electrochemical
events at the cell membrane and the activity patterns in neural networks feed
back on gene networks? As a model system for addressing
these issues, we study the neural circuit that controls circadian rhythms of locomotor
activity in Drosophila melanogaster. This neural circuit contains a number of
anatomically identifiable interconnected subsets of pacemaker neurons, each of
which contains a cell-autonomous molecular clock comprising interlocking feedback
loops of gene transcription, translation, and post-translational processing. In
our most recent studies, we have applied reverse genetic approaches to modifying
pacemaker membrane properties in which various fluorescently-tagged ion channel
subunits are ectopically expressed in the pacemaker neurons of transgenic flies
using a cell-specific promoter (see Figure). These studies indicate that electrochemical
events at the pacemaker membrane are part of another feedback loop that is essential
for circadian clock oscillation, and that regulates both the period and intercellular
synchrony of the clock. 
Our
working hypothesis is that Ca2+ influx through voltage-gated Ca2+ channels is
the means by which the pacemaker cell membrane interacts with the molecular oscillator.
We are currently testing this hypothesis by visualizing Ca2+ levels in the pacemaker
neurons using cell-specific expression of fluorescent Ca2+ sensor proteins. We
are also using genetic screening approaches to identify Ca2+-sensitive signaling
pathways that are involved in transducing changes in intracellular Ca2+ into effects
on transcription of clock genes. Additional areas
of interest in the Nitabach laboratory include:
(1) analysis of emergent
properties of the circadian control circuit that are modulated by the excitability
of its constituent neurons; (2) the cell biology of clock protein ubiquitination
and the role of de-ubiquitinating enzymes in regulating the molecular clock;
(3) systems-level forward-genetic analysis of ion channel synthesis, processing,
plasma membrane targeting, and biophysical modulation. Recent
publications: Nitabach, M.N., Blau, J., and Holmes, T.C. (2002).
Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian
clock. Cell 109: 485-495.
(See also van den Pol, A.N. and Obrietan, K.
(2002). News
and Views: Short circuiting the circadian clock. Nature Neurosci. 5: 616-618) Nitabach,
M.N. and Blau, J. (2002). Cellular
clockwork. Nature Genetics 32: 559-560 Nitabach, M.N., Llamas,
D.A., Thompson, I.J., Collins, K.A., and Holmes, T.C. (2002). Phosphorylation-dependent
and -independent modes of modulation of Shaker-family voltage-gated potassium
channels by Src-family protein tyrosine kinases. J. Neurosci. 22: 7913-7922 Nitabach,
M.N., Llamas, D.A., Araneda, R.C., Intile, J.L., Thompson, I.J., Zhou, Y.I., and
Holmes, T.C. (2001). A
mechanism for combinatorial regulation of electrical activity: Potassium channel
subunits capable of functioning as SH3-dependent adaptors. Proc. Nat'l Acad.
Sci. (USA) 98: 705-710 Nitabach MN, Blau J, Holmes TC. Electrical
silencing of Drosophila pacemaker neurons stops the free-running circadian clock.
Cell. 2002 May 17;109(4):485-95. Nitabach MN, Wu Y, Sheeba V, Lemon
W, Strumbos J, Zelensky P, White B, Holmes TC. Neuropeptide-secreting pacemaker
neurons synchronize independent circadian oscillators in the fly brain. Submitted.
Harrisingh M and Nitabach MN. Cytoplasmic calcium signaling is a
component of the free-running circadian oscillator. In preparation. Michael.Nitabach@yale.edu
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