Joshua M. Kaplan

Department of Genetics
Massachusetts General Hospital
Department of Molecular Biology
Simches 7
185 Cambridge Street
Boston, MA 02114
Tel: (617) 726-5900
Fax: (617) 726-5959
Email: kaplan@molbio.mgh.harvard.edu
Web Page: The Kaplan Lab Page
5 postdoctoral fellows, 4 graduate students

Work in my lab is focused on understanding how signals in the brain lead to particular patterns of behavior.  We utilize a combination of behavioral, genetic, biochemical, imaging, and electrophysiological techniques to study signaling in the brain of the worm C. elegans. Current projects include:

Presynaptic mechanisms. To identify new presynaptic components, and potential G proteins targets, we conducted two systematic RNAi screens.  In one screen, we looked for genes that whose inactivation decreased muscle activity, identifying 132 new proteins required for synapse structure and function.  In a second screen, we looked for genes whose inactivation increases muscle activity, identifying 93 genes.  We have shown that many of these genes alter muscle activity by disturbing the balance between synaptic excitation (at cholinergic NMJs) and inhibition (at GABAergic NMJs).  Characterizing these genes will provide new insights into how the excitation-inhibition balance is set.  Changes in this balance are thought to play a crucial role in several cognitive and neurological disorders, e.g. autism and epilepsy.  We hope that genes identified in our screens will yield new insights into the mechanisms underlying these disorders.

Regulation of insulin and neuropeptide secretion.  Insulin secretion, and its misregulation, plays a pivotal role in aging, diabetes, and obesity.   We have developed assays for insulin secretion in intact worms.  Using these assays, we have begun characterizing mechanisms regulating insulin secretion, and genetic screens to identify new genes that regulate insulin secretion.  Current projects aim to identify factors that differentially regulate secretion of classical neurotransmitters versus secretion of neuropeptides (e.g. insulin).

microRNA regulation of synaptic transmission.  We recently showed that a conserved microRNA miR-1 acts in mature muscle to regulate synaptic transmission.  miR-1 alters synaptic transmission by regulating a retrograde synaptic signal from muscle that inhibits neurotransmitter release from motor neurons.  Activation of muscle nicotinic acetylcholine receptors (nAChRs) induces the retrograde signal, and this effect requires the activity of the muscle transcription factor MEF-2.  miR-1 regulates mRNAs encoding two nAChR subunits, as well as the MEF-2 mRNA, thereby regulating the retrograde signal.  Current projects aim to determine how muscle activity regulates the retrograde signal, to identify MEF-2 targets involved in the retrograde signal, and to determine the pre-synaptic targets of the retrograde signal.

References:

• Sieburth, D., J.M. Madison, and J.M. Kaplan. (2007) PKC-1 regulates secretion of neuropeptides. Nat Neurosci, 10(1): 49-57.
• Ch'ng, Q., Sieburth, D., and Kaplan, J. M. (2008). Profiling synaptic proteins identifies regulators of insulin secretion and lifespan. PLoS Genet 4, e1000283.
• Vashlishan, A. B., Madison, J. M., Dybbs, M., Bai, J., Sieburth, D., Ch'ng, Q., Tavazoie, M., and Kaplan, J. M. (2008). An RNAi screen identifies genes that regulate GABA synapses. Neuron 58, 346-361.
• Simon, D. J., Madison, J. M., Conery, A. L., Thompson-Peer, K. L., Soskis, M., Ruvkun, G. B., Kaplan*, J. M., and Kim, J. K. (2008). The microRNA miR-1 regulates a MEF-2-dependent retrograde signal at neuromuscular junctions. Cell 133, 903-915.  *Corresponding author